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Chart 45.1: formation of alanine and glutamine by muscle

Chart 45.1: formation of alanine and glutamine by muscle

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glycolysis

aspartate



COO-



COO-



HCOPO32-



H3+NCH

H2C

α-ketoglutarate



CH2OH

2-phosphoglycerate



COO-



aspartate

aminotransferase



glutamate



GTP



COOC



O



malate

dehydrogenase



NAD+



NAD+



COO-



CHOH



C

lactate

dehydrogenase



CH3

lactate



α-ketoglutarate



H3+NCH



alanine

aminotransferase



pyruvate



malate/

aspartate

shuttle



CHOH

H2C COO-



NADH+H+



malate

dehydrogenase



malate



COOC



O



H2C COOoxaloacetate



C



H2O



citrate

synthase



acetyl CoA



SCoA



acetyl CoA



H2C



CoA



citrate



H2O



CH2COOCH COO2



O

COO-



C



(CH3)2CH



α-ketoisovalerate



α-ketoisocaproate



FAD

FADH2



CO2



CO2



O

C



(CH3)2CH



SCoA



FAD

FADH2



succinate

CoASH GTP



GDP+Pi



O C SCoA

succinyl CoA



CO2



NADH

H+



CH2COO-



CH2COOCH3CH



H2O



hydratase



NADH+H+



OH CH3 O

C



CH3 CH



C



α-methyl-β-hydroxybutyryl CoA



acyl-CoA

dehydrogenase



FAD

FADH2



CH2



H2O



CH2



H3+N



CH



O



COO-



NADH+H+



CO2

CoASH



ATP



H2O

hydrolase



H O

CH3(CH2)12 C



-OOC



CH2 C



C



SCoA



SCoA



trans-Δ2-enoyl-CoA



enoyl-CoA

hydratase



O

CH2 C



C



H



hydratase



H2O



OH



O



CH3(CH2)12 CH



CH2 C



SCoA



L-3-hydroxyacyl CoA



CH3



β-hydroxy-β-methylglutaryl CoA

(HMGCoA)



ADP+P



acetyl CoA

acyl transferase



i



L-3-hydroxyacyl CoA

dehydrogenase



dehydrogenase



NAD+

+

NADH+H



O



HC CH2 COOmethylmalonate

semialdehyde

CoASH



glutamine synthetase

NH4+



H2O



OH



β-hydroxyisobutyryl CoA



SCoA



β-methylglutaconyl CoA



hydratase



SCoA



C



CH3



SCoA



CH2 CH C



CH



O CH3



CH3 O



CH3 C CH C SCoA

α-methylacetoacetyl CoA



glutamine



glutamate



H2O



O



CH2 C



NAD+

dehydrogenase



NADH+H+



CH2CONH2



glutaminase



CH COO-



carboxylase



β-hydroxyisobutyrate

NAD+



CH2COO-



C



C



methylacrylyl CoA



CoASH



glutamate

dehydrogenase

H2O



CH2



OH CH3 O

SCoA



NH4+



+

NAD(P)H+H



H3+N



C C SCoA

tiglyl CoA



NAD+



-OOC



CH3 O



CH3 O



O C COOα-ketoglutarate



NAD(P)+



SCoA



palmitoyl CoA



H2O



CO2

ATP



CO2



CH2



NAD+ CoASH



CH3(CH2)12 CH2 CH2 C



FADH2



ADP+Pi



HOCH COOisocitrate



α-ketoglutarate

dehydrogenase



CH2



O

SCoA



FAD



isovaleryl CoA

dehydrogenase



[cis-aconitate]



isocitrate

dehydrogenase

Mg2+



CH2COO-



CoASH



(CH3)2C CH C SCoA

β-methylcrotonyl CoA



Krebs cycle

succinyl CoA

synthetase



carnitine



inner CAT



isovaleryl CoA



isobutyryl CoA

isobutyryl CoA

dehydrogenase



outer CAT



O

CH2 C



(CH3)2CH



CoASH



acyl CoA synthetase



palmitoylcarnitine



NAD+

branched chain α-ketoacid

dehydrogenase

NADH+H+



CoASH



ATP



PPi+AMP



palmitoyl CoA



carnitine

shuttle



NAD+

branched chain α-ketoacid

dehydrogenase

NADH+H+



CoASH



COO-



CH2 C



(CH3)2CH



carnitine

shuttle



CH3 O



HC COO-



succinate

dehydrogenase



FAD



branched-chain

amino acid

aminotransferase



glutamate



aconitase



H2O



fumarate



CH COO+NH

3



CH2



α-ketoglutarate



aconitase



HCCOO-OOCCH



FADH2



CH3 CH



O



COO-



fumarase



H2O



3



branched-chain

amino acid

aminotransferase



glutamate



CH3



COO-



O



NAD+

branched chain α-ketoacid

dehydrogenase

NADH+H+



α-methylbutyryl CoA

dehydrogenase



CH2COOHOC COO-



CH

+NH



α-ketoglutarate



COO-



C



CH3CH2 CH C SCoA

α-methylbutyryl CoA



O

H3C



NAD+



CO2



NADH+H+



CO2



HCO3-



COO-



pyruvate dehydrogenase



CH



3



carnitine

shuttle



NAD+



thiamin PP

lipoate

riboflavin



ADP+P

i



dicarboxylate

carrier

CoASH



CoASH

pyruvate carboxylase

(biotin)



CH



CH3



α-keto-β-methylvalerate



alanine



pyruvate

carrier



ATP



CH3 O

CH3CH2



CH3



leucine



CH3



COO-



branched-chain

amino acid

aminotransferase



glutamate



COO-



O



CH3



dicarboxylate

carrier



α-ketoglutarate



glutamate



COO-



NADH+H+



HCOH



H2C COOmalate



CH3CH2CHCH

+NH



pyruvate

kinase

Mg2+ K+



ATP



COO-



CH3



CH2

phosphoenolpyruvate

ADP



valine



isoleucine



COPO32-



phosphoenolpyruvate

carboxykinase



H2C COOoxaloacetate

NADH+H+



COO-



CO2



GDP



The branched-chain amino acids



Cytosol



enolase

Mg2+



H2O



O



CH3(CH2)12 C CH2 C SCoA

3-ketoacyl CoA



NAD+

dehydrogenase

+

NADH+H



O

CH3(CH2)12 C



O



CoASH



SCoA



thiolase



myristoyl CoA



CH3CH2C SCoA

propionyl CoA

CO2

ATP



carboxylase



ADP+Pi



D-methylmalonyl CoA

racemase



acetyl CoA



Mitochondrion



acetyl CoA



acetyl CoA

acetoacetyl CoA

thiolase



HMGCoA lyase



L-methylmalonyl CoA

mutase (vit B12)



acetoacetyl CoA



succinyl CoA

β-ketoacyl-CoA transferase (not in liver)



O

H3C C SCoA

acetyl CoA



acetyl CoA

acetoacetate



β-oxidation



succinate



Chart 45.1  Formation of alanine and glutamine by muscle.



Part 5  Amino acid metabolism



91



palmitate



Catabolism of amino acids II



46



Alanine.  Alanine is in equilibrium with pyruvate, which is oxidatively

decarboxylated to CO2 and acetyl CoA. The latter can then be oxidized in

Krebs cycle (Chart 46.1).

Glycine.  Although there are several possible routes for glycine

catabolism, the mitochondrial glycine cleavage system is probably the most

important in mammals. This enzyme complex is loosely bound to the

mitochondrial inner membrane and has several similarities to the pyruvate

dehydrogenase complex. It oxidatively decarboxylates glycine to carbon

dioxide and N5,N10‐methylene‐tetrahydrofolate.

Serine.  When needed as a respiratory fuel, serine undergoes deamination

by serine dehydratase to form pyruvate.

Threonine.  The most important route for the catabolism of threonine in

humans is via the threonine dehydratase pathway to form α‐ketobutyrate.

This is metabolized to succinyl CoA, as outlined for methionine metabolism.

In experimental animals the aminoacetone pathway is the major pathway

for threonine catabolism. Threonine dehydrogenase forms the unstable

intermediate 2‐amino‐3‐oxobutyrate, which is spontaneously decarboxylated

to aminoacetone for further catabolism to pyruvate.

Cysteine.  There are several possible pathways for cysteine degradation

but the most important in mammals is oxidation by cysteine dioxygenase to

cysteine sulphinate. This is then transaminated to form 3‐sulphinylpyruvate

(also known as β‐mercaptopyruvate or thiopyruvate), which is converted to

pyruvate in a spontaneous reaction.

Methionine.  Methionine is activated in an ATP‐dependent reaction to

form S‐adenosylmethionine (SAM), which is the major carrier of methyl

groups, beating tetrahydrofolate (THF) into second place as a donor in



Chart 46.2  For complete oxidation,

amino acids must be converted to

acetyl CoA. If amino acids are to be

used as a respiratory fuel it is

obligatory that their carbon

skeletons are converted to acetyl

CoA, which must then enter Krebs

cycle for oxidation, producing ATP as

described in Chapter 6. NB: The

simple entry of the carbon skeletons

into Krebs cycle as ‘dicarboxylic

acids’ (α‐ketoglutarate, succinate,

fumarate or oxaloacetate) does not

ensure their complete oxidation for

energy metabolism.



aspartate

phenylalanine*

tyrosine*



Glycolysis



C



NADH

H+

fumarate



O



Cytosol



CO2



GDP



GTP



COO-



COOCOPO32-



phosphoenolpyruvate

carboxykinase



H2C COOoxaloacetate



CH2

phosphoenolpyruvate



NAD+



ATP



COO-



COO-



NADH+H+



NAD+



COO-



CHOH



C



HCOH



H2C COOmalate



lactate

dehydrogenase



CH3

lactate



O



CH3



pyruvate



dicarboxylate

carrier



malate/

aspartate

shuttle



pyruvate

carrier

CoASH

ATP



Mitochondrion



HCO3-



H3C



C



H2C COO-



malate

dehydrogenase



SCoA



O



H2C COO-



malate



C



acetyl CoA



COO-



CHOH



NADH+H+

O



NADH+H+

NAD+



phenylalanine*

tyrosine*

tryptophan*

isoleucine*

lysine

leucine



pyruvate dehydrogenase



CO2



ADP+P

i



COO-



NAD+



thiamin PP

lipoate

riboflavin



pyruvate carboxylase

(biotin)



H O

2



oxaloacetate



citrate

synthase



CH2COOCOO-



HOC

CoASH



H2C



aconitase



COO-



citrate



H2O



[cis-aconitate]

aconitase



fumarase



H2O



fumarate



FADH2



NADH+H+



succinate

dehydrogenase

FAD



CO2



GTP

succinyl CoA

synthetase



CH2COOCH COO-



CH2COO-



CoASH



GTP



O C SCoA

succinyl CoA



Pi

GDP



HOCH COOisocitrate



CO2



O C COOα-ketoglutarate



NADH+H+



* indicates which amino acids are

both glucogenic and ketogenic.

Ketogenesis from amino acids is

summarized in Chart 36.1



92



isoleucine*

valine

methionine



NAD+



CH2COOCH2



NAD+ CoASH



CH2COO-



HC COO-



isocitrate

dehydrogenase

Mg2+

α-ketoglutarate

dehydrogenase



CH2



2



succinate



H2O



Krebs

cycle



HCCOO-OOCCH



FADH2



tryptophan*

alanine

cysteine

serine

threonine

glycine



pyruvate

kinase

Mg2+ K+



ADP

malate

dehydrogenase



glutamate, proline

histidine, arginine



NADH+H+

CO2



biosynthetic methylations. For example, SAM is used in the methylation

of noradrenaline to adrenaline by noradrenaline N‐methyltransferase.

Consequently, the original methionine molecule is demethylated to form

S‐adenosylhomocysteine, then the adenosyl group is removed to

homocysteine. This intermediate can be metabolized in two ways:

1 It can be recycled to methionine in a salvage pathway where the methyl

donor is N5‐methyl‐THF, using a vitamin B12‐dependent reaction catalysed by homocysteine methyltransferase. This is an important pathway

that helps to conserve this essential amino acid.

2 It can be degraded to succinyl CoA, which can be further metabolized to

pyruvate for energy metabolism.

Lysine.  Lysine is unusual in that it cannot be formed from its corresponding

α‐ketoacid, α‐keto‐ε‐aminocaproic acid, which cyclizes to form Δ1‐piperidine‐2‐

carboxylic acid. Degradation of lysine occurs via saccharopine, a compound in

which lysine and α‐ketoglutarate are bonded as a secondary amine formed with

the carbonyl group of α‐ketoglutarate and the ε‐amino group of lysine.

Following two further dehydrogenase reactions, α‐ketoadipate is formed by

transamination. This enters the mitochondrion and is oxidized by a pathway

with many similarities to the β‐oxidation pathway. Acetoacetyl CoA is formed,

thus lysine is classified as a ketogenic amino acid (see Chapter 36).

Tryptophan.  Although tryptophan can be oxidized as a respiratory

fuel, it is also an important precursor for the synthesis of NAD+ and

NADP+ (see Chapter 50). The regulatory mechanisms involved in the first

step of tryptophan catabolism catalysed by tryptophan dioxygenase (also

known as tryptophan pyrrolase) have been studied extensively. It is known

that the dioxygenase is induced by glucocorticoids, which increase

transcription of DNA. Furthermore, glucagon (via cyclic adenosine

monophosphate, cAMP) increases the synthesis of dioxygenase by

enhancing the translation of mRNA. Hence in starvation, the combined

effects of these hormones will promote the oxidation of tryptophan

released from muscle protein.

During the catabolism of tryptophan, the amino group is retained in

the  first three intermediates formed. The amino group in the form of

alanine is then hydrolytically cleaved from 3‐hydroxykynurenine by

­

kynureninase. This alanine molecule can then be transaminated to

­pyruvate, thus  ­qualifying tryptophan as a glucogenic amino acid. The

other p

­ roduct of kynureninase is 3‐hydroxyanthranilate, which is degraded

to α‐ketoadipate. This is oxidized by a pathway that is similar to β‐oxidation

to form acetoacetyl CoA. Hence tryptophan is both a ketogenic and a

­glucogenic amino acid.

Glutamate.  This readily enters Krebs cycle following oxidative

deamination by glutamate dehydrogenase as α‐ketoglutarate. However, for

complete oxidation its metabolites must temporarily leave the cycle for

conversion to pyruvate. This can then be oxidized to acetyl CoA, which

enters Krebs cycle for energy metabolism, generating ATP.

Histidine.  Histidine is metabolized to glutamate by a pathway that

involves the elimination of a 1‐carbon group. In this reaction, the formimino

group (–CH = NH) is transferred from N‐formiminoglutamate (FIGLU) to

THF, yielding N5‐formimino‐THF and glutamate.

Arginine.  This amino acid is a constituent of proteins as well as being an

intermediate in the urea cycle. Arginine is cleaved by arginase to liberate

urea, and ornithine is formed. Ornithine is transaminated by ornithine

aminotransferase to form glutamate γ‐semialdehyde. The semialdehyde

is  then oxidized by glutamate γ‐semialdehyde dehydrogenase to form

glutamate.

Proline.  The catabolism of proline to glutamate differs from its

biosynthetic pathway. Proline is oxidized by the mitochondrial enzyme

proline oxygenase, to form pyrroline 5‐carboxylate. This is probably an

FAD‐dependent enzyme, located in the inner mitochondrial membrane,

which can donate electrons directly to cytochrome c in the electron transport

chain.



Metabolism at a Glance, Fourth Edition. J. G. Salway. © 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.



COO-



3



NH



H3+NCH

CH2



CH

+NH



COO-



ADP



3



ATP



O2



tetrahydrobiopterin

4-monooxygenase



H2O



dihydrobiopterin



CH2



CH

+NH



Cytosol



NADP+

dihydrobiopterin

reductase

NADPH+H+



HCOH



COOCOO-



3



α-ketoglutarate



2



aspartate

aminotransferase



glutamate



dioxygenase



C



O



H2C

oxaloacetate



1,2 dioxygenase



NADH+H+



4-maleylacetoacetate



COO-



fumarylacetoacetate

fumarylacetoacetase



fumarate



acetoacetate



H2O



oxidized by

extrahepatic tissues



alanine

aminotransferase



CH3



alanine



dioxygenase



dehydratase

H2O

+

NH4



CH3



pyruvate



HCO3-



NADH+H+



C



malate

dehydrogenase



O

COO-



H 2C



malate



NADH+H+



C



oxaloacetate



H2O



NADH+H+



3



CH2COOHOC COOH2C



CoA



alanine

pyruvate



glycine



citrate



H O

2



H2O



serine-pyruvate

aminotransferase



CH2COO-



succinyl CoA

synthetase



CH2COO-



CH2COO-



α-ketoglutarate

dehydrogenase



CoASH GTP



GDP+Pi



CO



2



NADH

+

H



ATP



1



/ 2 O2



2H+



O C SCoA

succinyl CoA



H2O



ADP



NAD



isocitrate

dehydrogenase

Mg2+



NAD+



NAD(P)H+H+

glutamate dehydrogenase

NAD(P)+



+

NH4



H2O



glutamate



F1



glycine cleavage enzyme

or glycine synthase



+



NADH+H



NH +

4

N5,N10-methylene

THF



racemase



FADH2



CH2



C



+



-OOCCH CH

2

2



CH3 C



carbamoyl phosphate

synthetase

HCO 3



(vit B12)

C



i



carbamoyl

phosphate



urea

cycle



NADH

+

H



glutamate

γ-semialdehyde

dehydrogenase



+



NAD



glutamate

γ-semialdehyde



CH2COOH3+N



P5C synthetase

ADP

Pi



+



NADP



NADPH

ATP

+

H



CH2

CH



COO-



histidine



NH +

4



COOH +NCH



ATP



lyase



urocanate

hydratase



H2O



4-imidazolone5-propionate



imidazolone

propionase



THF



glutamate

formiminotransferase



FIGLU

(N-formiminoglutamate)



H O

SCoA



C



CH3(CH2)12 C



C



enoyl-CoA

hydratase



NADH+H+



CH3(CH2)12 C

H



CoASH

thiolase



H O

2



CH2 C



SCoA



L-3-hydroxyacyl CoA



L-3-hydroxyacyl CoA

dehydrogenase



+



NAD



NADH+H+



O



O



C CH2 C SCoA

acetoacetyl CoA



SCoA



O



OH



NAD



SCoA



C



2

H trans-Δ -enoyl-CoA



O



CH3(CH2)12 C CH2 C SCoA

3-ketoacyl CoA

O

CH3(CH2)12 C



CoASH



SCoA



thiolase



myristoyl CoA

O



O

H3C



C



SCoA



acetyl CoA



H3C C SCoA

acetyl CoA



β-oxidation



H3+NCH



NH2



urea



fumarate



COO-



(CH2)3

ornithine



H2O



AMP+PPi



FAD

FADH2



SCoA



O



O



argininosuccinate



3



glutamate



N5-formimino-THF



C



H2O



O



spontaneous



histidase



C



hydratase



CH3



aspartate

synthetase



SCoA



CO

2



dehydrogenase



H3C



ornithine



NH



glutaconyl CoA



CH3 CH CH2 C SCoA

3-hydroxybutyryl CoA



ornithine

transcarbamoylase



pyrroline 5-carboxylate (P 5-C)



acyl-CoA

dehydrogenase



crotonyl CoA



acetyl CoA



CH COO+NH

3



H



+



P



FAD



CH2



C



OH



SCoA



C



glutamate

aminotransferase

α-ketoglutarate



C



C



H



succinyl CoA



citrulline

2ATP 2ADP+P

i



FAD



H O



SCoA



O

NAD



CH2 CH2 C

palmitoyl CoA



FADH2



spontaneous



L-methylmalonyl CoA

mutase



CH3(CH2)12



H O

-OOC



CH3



CO2



SCoA



acyl-CoA

dehydrogenase



-OOCCH C SCoA

D-methylmalonyl CoA



-OOCCH



O



C



glutaryl CoA



IV



proline



NH4+



NADH+H+



O



THF



2



O C COOα-ketoglutarate



+ CoASH



F0



NADPH

+

H



reductase



+



NAD



O



-OOC(CH )

2 3



SCoA



CH3 O

H2O



NADH+H+



CO



CH2



CH2



succinate



+

NADP



2-aminomuconate



NADH+H+



NAD+



CO2



CO2

carboxylase



ATP



THF



CH2COOHC COO-



CoASH

α-ketoadipate

dehydrogenase



NADH+H+



O



ADP+Pi



HOCH COOisocitrate



succinate

dehydrogenase



CH2COO-



N



O

-OOC (CH )

C COO2 3

α-ketoadipate



NAD+



CH3CH2 C



serine

hydroxymethyl

transferase



[cis-aconitate]



acetyl CoA is

oxidized in

Krebs cycle



fumarate



COO-



aminotransferase

glutamate



propionyl CoA



serine



aconitase



COO-



2



aconitase



HCCOO-OOCCH



reductase



spontaneous



dehydrogenase



NADH+H+



α-ketoglutarate



deaminase



NH4+



2-aminomuconate

semialdehyde

NAD+



2-aminoadipate



homoserine



NAD+ and NADP+

synthesis

(see Chapter 42)



CO2



dehydrogenase



NADH+H+



cysteine



CO2



N5,N10-methylene

THF

dehydrogenase



3-hydroxypyruvate



fumarase



Mitochondrion



kinase



glycerate



SCoA



citrate

synthase



H +NCH



ATP

NAD+



acetyl CoA



COO-



CHOH

COO-



ADP



O

H 3C



NAD+



COO-



+

N

H2



2 aminoadipate

semialdehyde



H2O



cystathionase



3,4-dioxygenase



2-amino-3-carboxymuconate

semialdehyde

picolinate

carboxylase



NAD+



cystathionine

synthase



CoASH

α-ketobutyrate

dehydrogenase



COO-



2-phosphoglycerate



pyruvate dehydrogenase



CO2



ADP+Pi



proline oxygenase



2



α-ketobutyrate



NAD+



thiamine PP

lipoate

riboflavin



pyruvate carboxylase

(biotin)



FAD



threonine



glutamate



O



saccharopine dehydrogenase

(both mono- and bifunctional)



NADH+H+



cystathionine



CH3



spontaneous



CoASH



FADH2



CHOH



3-hydroxyanthranilate



H2O

NAD+



kynureninase



alanine



H2O



saccharopine



glutamate



H2O



H2O

H2O



pyruvate

carrier



ATP



H O

2



+

NH4



3-sulphinylpyruvate



2- H O

SO3

2



+



adenosyl

homocysteinase



serine



3-monooxygenase

(outer mitochondrial

membrane)



3-hydroxykynurenine



lysine-α-ketoglutarate

reductase (bifunctional)



NADP



methyl

transferase



homocysteine



H3+NCH



aminotransferase



COO-



NADPH+H+



adenosine



H2O



O2

NADPH+H+



α-ketoglutarate



adenosyl

transferase



H2O



COO-



dehydratase



H2O



formamidase



kynurenine



This pathway probably occurs in

both the cytosol and mitochondrion



S-adenosylhomocysteine



α-ketoglutarate



pyruvate

kinase

Mg2+ K+



dicarboxylate

carrier



H2C



THF



cysteine sulphinate



C O



3



H2C COOmalate



fumarase



CH2

phosphoenolpyruvate



H +NCH



CHOH



O2



COPO32-



ATP

α-ketoglutarate

glutamate



COO-



cysteine



methionine

Pi+PPi



H2O

HCOO-



lysine



CH3



S-adenosylmethionine



serine



SH



COO-



ADP



malate

dehydrogenase



NAD+



isomerase



CO2



GDP



phosphoenolpyruvate

carboxykinase



COO-



homogentisate



H O

2



GTP



COO-



CO2

O2



H2O



S



ATP



2,3-dioxygenase



N-formylkynurenine



CH2

+NH

3



CH2



methyl group

transferred to

acceptor



CH2OH



CH2



CH2



CH2



THF



“salvage

pathway”



serine

hydroxymethyl

transferase



H3+NCH



N3+NCH



enolase

Mg2+



N5-methyl

THF



N5,N10-methylene

THF



COO-



COO-



CH2OH

2-phosphoglycerate



aspartate



glycine



Pi



COO-



COO-



4-hydroxyphenylpyruvate



COOH3+NCH2



phosphatase



HCOPO32-



CH2



tyrosine

aminotransferase



3-phospho

serine



3-phosphoserine

α-ketoglutarate

aminotransferase



phosphoglycerate

Mg2+ mutase



tyrosine



O



3-phospho

hydroxypyruvate



(vit B12)



O2



CH2



H3+NCH



homocysteine

methyltransferase



H2O



OH



glutamate



α-ketoglutarate

glutamate



NADH+H+



dehydrogenase



CH2OPO323-phosphoglycerate



H3+NCH



α-ketoglutarate



NAD+



COO-



phenylalanine



biosynthesis of

nucleotides, creatine,

porphyrins, glutathione



phosphoglycerate

kinase



tryptophan



CH2



COO-



1,3-bisphosphoglycerate



COO-



CH2 CH

+NH



glycolysis



(CH2)3

arginase



NH

NH2



C

+NH



2



arginine



Chart 46.1  Catabolism of amino acids.



Part 5  Amino acid metabolism



93



picolinate



Metabolism of amino acids to glucose in starvation and during the period

immediately after refeeding



47



In liver, the switch from gluconeogenic mode to

glycolytic mode in the early fed‐state is a slow process

During starvation, when the glycogen reserves have been exhausted, muscle

proteins are degraded to amino acids and used by the liver for gluconeogenesis to maintain the supply of glucose, which is vital for the brain. The important role of alanine as a gluconeogenic precursor is described in Chapter 45.

Following refeeding after a period of starvation, the liver does not switch

instantaneously from gluconeogenic to glycolytic mode even though it

receives a large glucose load from the intestines. In the early fed state the

effects of the gluconeogenic and lipolytic hormones linger, and β‐oxidation

of fatty acids continues. Consequently, large quantities of acetyl CoA are

produced, which inhibit pyruvate dehydrogenase, thereby favouring gluconeogenesis in liver. Under these conditions, the amino acids derived from

the gastrointestinal digestion of dietary protein can be used for gluconeogenesis, as shown in Chart 47.1 and described below.



Starvation



Diagram 47.1  Intermediary

metabolism in the early fed state.

β‐Oxidation of fatty acids continues

in the early fed state. The liver

continues in ketogenic and

gluconeogenic modes, using lactate

(from muscle) and dietary amino

acids as gluconeogenic substrates.

Muscle uses fatty acids and ketone

bodies as respiratory fuels. Also,

glycolysis is active in muscle but,

since pyruvate dehydrogenase is

inactive, lactate is formed.



In starvation, hepatic gluconeogenesis is active under the hormonal

­influence of glucagon, cortisol and adrenocorticotropic hormone (ACTH)

(see Chapter 18). Glycolysis in liver is inhibited because glucagon, through

protein kinase A (cAMP‐dependent protein kinase), causes the

­phosphorylation of hepatic pyruvate kinase, thereby causing inhibition.

Moreover, the phosphorylation of hepatic pyruvate kinase is potentiated by

its allosteric effector alanine (which is abundant in starvation), which therefore further enhances the inhibition of pyruvate kinase.



Role of acetyl CoA in promoting gluconeogenesis

in starvation



but is instead carboxylated by pyruvate carboxylase to oxaloacetate for metabolism to phosphoenolpyruvate and thence to glucose via gluconeogenesis.



Early fed state

Fate of the glucogenic amino acids



During refeeding after a period of starvation, the liver remains in the gluconeogenic mode for a few hours. Consequently, the glucogenic amino acids

derived from dietary protein are metabolized to 2‐phosphoglycerate, which is

their common precursor for gluconeogenesis (Chart 47.1 and Diagram 47.1).

NB: Evidence suggests that gluconeogenesis from serine originates in the

­mitochondrion. However, the mitochondrial carriers needed for the route shown,

in particular the 2‐phosphoglycerate carrier, have not been characterized.

In any event, 2‐phosphoglycerate is metabolized to glucose 6‐phosphate,

which can be used to synthesize glycogen or glucose. The amino nitrogen

derived from the amino acids is detoxified as urea.



Dietary glucose is converted by muscle to lactate prior

to glycogen synthesis



It is emphasized that, in the early fed state, glucose cannot be used by the

liver for glycolysis. Instead, high concentrations of glucose promote hepatic

glycogen synthesis. Alternatively, in the presence of insulin, ­glucose enters

the muscle cells where it undergoes glycolysis to lactate (Diagram 47.1).

Remember that β‐oxidation of fatty acids is active and produces an abundance of acetyl CoA, which inhibits muscle pyruvate dehydrogenase. This

means that lactate is formed even though conditions are aerobic. The lactate

is then transported to the liver, which can convert it to glycogen or glucose.



During starvation, β‐oxidation from fatty acids is very active in the liver, and

large quantities of acetyl CoA are formed. The accumulated acetyl CoA inhibits pyruvate dehydrogenase and stimulates pyruvate carboxylase. This means

that pyruvate (derived from alanine) does not enter Krebs cycle as acetyl CoA,



glucose



glycogen



dietary glucose



glucose



Muscle



glucose



Liver



lactate



pyruvate



amino

acids



ketone

bodies



94



fatty acids

lactate

ketone

bodies



acetyl CoA



α-keto

glutarate



fatty acids



amino

acids



β-Oxidation



Glycolysis



β-Oxidation



Gluconeogenesis



pyruvate

pyruvate

dehydrogenase

inactive



acetyl CoA



Krebs cycle



Metabolism at a Glance, Fourth Edition. J. G. Salway. © 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.



glucose,

or glycogen in liver



+



NH3



NH



H3+NCH

CH2 CH







1,3-bisphosphoglycerate



COO



+



NH3



ADP



O2



4-monooxygenase

dihydrobiopterin





CH2 CH



Cytosol



NADP+

dihydrobiopterin

reductase

NADPH+H+



tetrahydrobiopterin



H2O



aspartate



2-phosphoglycerate



glutamate



dioxygenase



C



homogentisate



O



1,2 dioxygenase



NADH+H+



malate

dehydrogenase



NAD+



COO-



fumarylacetoacetate

fumarylacetoacetase



H2O



fumarate



acetoacetate



CHOH



oxidised by

extrahepatic tissues



CH2

phosphoenolpyruvate

pyruvate

cAMP

ADP

kinase

alanine

COO



alanine

aminotransferase



CH3



alanine



CH3



threonine



3-sulphinylpyruvate



H2O

NH4+



CH3



pyruvate



pyruvate carboxylase



(biotin)



acetyl CoA



CO2



NADH+H+



NADH+H+



C



malate

dehydrogenase



O



H2C COO–



malate



oxaloacetate



aminotransferase



glutamate



fumarase







OOC(CH2)3 C COO–

α-ketoadipate



OOCCH

fumarate



CH2



CH2COO–



COO–



H2C COO



CoA



COO







H3 NCH

CH2

CONH2



GTP



CoASH



GDP+Pi



CH2COO–



α-ketoglutarate

dehydrogenase



CO2



NADH

H+



ATP



O2



Mitochondrion



O C SCoA

succinyl CoA



H2O ADP



O C COO–

α-ketoglutarate



NAD(P)H+H+

glutamate dehydrogenase

NAD(P)+



NH4+

H2O



glutamate



F1



CO2



CH2



NAD+ CoASH



F0



CH2COO–



N5,N10-methylene

THF







CH2



Pi



C



C



SCoA



C



C



C



H O

SCoA



hydratase



H2O



OH



O



CH3



CH CH2 C SCoA

3-hydroxybutyryl CoA



urea

cycle



proline



NAD+



glutamate

γ-semialdehyde

glutamate

aminotransferase

α-ketoglutarate



glutamate

γ-semialdehyde

dehydrogenase



NADH

H+



CH2COO–

CH2



H3+N CH

H COO–



P5C synthetase

ADP

Pi



NADP+



NADPH ATP

H+



COO–



N



NH



+NH



3



histidine



histidase



lyase



(CH2)3



H2O



urocanate



hydratase



H2O



4-imidazolone5-propionate



imidazoline

propionase



THF



glutamate

formiminotransferase



NH2



FIGLU

(N-formiminoglutamate)



urea



fumarate



SCoA

H O

2



C



O

CH2



C



SCoA



H L-3-hydroxyacyl CoA

NAD+



L-3-hydroxyacyl CoA

dehydrogenase



NADH+H+



O

CH3(CH2)12



O



C CH2 C SCoA

3-ketoacyl CoA



O

CH3(CH2)12



C



CoASH



SCoA



thiolase



myristoyl CoA

O

H3C C SCoA

acetyl CoA



β-oxidation



COO–

H3+NCH



ornithine

N5-formimino-THF



NH4+



AMP+PPi



ar

argininosuccinate



H3+NCH



glutamate



ornithine



CH2 CH



COO–



H3C C SCoA

acetyl CoA



C



2

H trans-Δ -enoyl-CoA



OH

CH3(CH2)12



CoASH

thiolase



O



spontaneous



C



O



C CH2 C SCoA

acetoacetyl CoA



O



ATP



C



enoyl-CoA

hydratase



NADH+H+



O

CH3



aspartate

aspar

synthetase



CH3(CH2)12



NAD+



H3C C SCoA

acetyl CoA



pyrroline-5-carboxylate (P5C)



SCoA



CO2



dehydrogenase



FAD



FADH2



glutaconyl CoA



H crotonyl CoA



ornithine

transcarbamoylase



FADH2



FAD



acyl-CoA

dehydrogenase



H O



succinyl CoA



citrulline



carbamoyl

phosphate



C



spontaneous



SCoA

CH3



OOCCH2CH2 C



SCoA



palmitoyl CoA



FAD



H



mutase

(vit B12 )



NAD+



carbamoyl phosphate

synthetase

HCO3–



OOC



L-methylmalonyl CoA



NADH+H+



CH2 CH2 C



H O





CH3

CO2



CH3(CH2)12



FADH2



O

OOCCH C



SCoA



acyl-CoA

dehydrogenase



carboxylase







O



C



glutaryl CoA



CO2



O



2ATP 2ADP+P

i



NADH+H+



OOC(CH2)3



racemase



THF



IV



C



proline oxygenase



isocitrate

dehydrogenase

2+

Mg



glycine cleavage enzyme

or glycine synthase



+

NADH+H

+

NH

4



HOCH COO–

isocitrate



CH2



succinate



NADPH

H+



NH4+



O







SCoA



CH3 O

-OOCCH C SCoA

D-methylmalonyl CoA



H2O



HC COO–



asparagine



CH2COO–



THF



[cis-aconitate]



+



synthetase

ATP

AMP+PPi



ADP+Pi



+

NAD

H2O



C



ATP



serine



aconitase







aconitase



aspartate

succinyl CoA

synthetase



CH2COO–



NADP+



reductase



NAD+



NAD+



CO2



O



propionyl CoA



THF

serine

e

hydroxymethyl

transferase



serine-pyruvate

aminotransferase



pyruvate



COO–



citrate



glutamate



H3 NCH



FAD



CH2COO

HOC



H2O



+



succinate

dehydrogenase



alanine







CoASH

α-ketoadipate

dehydrogenase



NADH+H+



CH3CH2



dehydrogenase

N5,N10-methylene



3-hydroxypyruvate



C SCoA



COO– glutamine







glycine



NAD+



aspartate

aminotransferase



α-ketoglutarate



HCCOO–



COO–



2-aminomuconate

NADH+H+



O



NAD+



CO2



glycerate



NADH+H+



citrate

synthase



H2O



kinase



ATP



acetyl CoA



acetyl CoA



COO–



CHOH

H2C COO–



ADP



O

H3C



NAD+



COO–



CoASH

α-ketoadipate

dehydrogenase



2-phosphoglycerate



NAD+



pyruvate

dehydrogenase



HCO3–



+

N

H2



picolinate



dehydrogenase



α-ketobutyrate



CoASH

thiamine PP

lipoate

riboflavin



ADP+Pi



reductase



spontaneous



NAD+



glutamate



deaminase



NH4+



2-aminomuconate

semialdehyde

NADH+H+



α-ketoglutarate



homoserine



dehydratase



CO2



dehydrogenase



2-aminoadipate



H2O

cystathionase



NAD+ and NADP+

synthesis



picolinate

carboxylase



NAD+

NADH+H+



cystathionine



cysteine



3,4-dioxygenase



2-amino-3-carboxymuconate

semialdehyde



2 aminoadipate

semialdehyde



cystathionine

synthase



H2O



CHOH



O2



glutamate



serine



H3+NCH



kynureninase



3-hydroxyanthranilate



saccharopine dehydrogenase

(both mono- and bifunctional)



NADH+H+



homocysteine



COO–



H2O

NH4+



H2O



H2O



adenosyl

homocysteinase



H2O



3-hydroxykynurenine



pyruvate

carrier



ATP



FADH2



saccharopine

NAD+



3-monooxygenase

(outer mitochondrial

membrane)



NADP+



alanine



H2O



adenosine



spontaneous



C O



H3 NCH



H2O



O2

NADPH+H+



lysine-α-ketoglutarate

reductase (bifunctional)



NADP+



S-adenosylhomocysteine



α-ketoglutarate

aminotransferase

glutamate



SO32– H2O







dehydratase



dioxygenase



cysteine sulphinate



Mg2+ K+



dicarboxylate

carrier



H2O



O2



COPO32–



ATP

α-ketoglutarate

glutamate



COO-



cysteine



NADPH+H+



formamidase



kynurenine



α-ketoglutarate



methyl

transferase



serine



SH



H2O

HCOO–



This pathway probably occurs in

both the cytosol and mitochondrion



adenosyl

transferase



Pi+PPi



methyl group

transferred to

acceptor



THF



CH2

NH3



H2O



ATP



CH2OH



CH2



COO–



+



H2C COO–

malate



fumarase



CO2



GDP



phosphoenolpyruvate

carboxykinase



H2C COO–

oxaloacetate



4-maleylacetoacetate



H2O



GTP



COO–



CO2

O2



H2O



H3+NCH



H3+ NCH



enolase

Mg2+



CH3



methionine



2,3-dioxygenase



N-formylkynurenine



lysine



S-adenosylmethionine



serine

hydroxymethyl

transferase



COO



COO–



CH2OH



aspartate

aminotransferase



N5,N10-methylene

THF







+



S



Salvage

pathway



glycine



CH2



CH2



COO–

H3+NCH2



Pi



HCOPO32-



α-ketoglutarate



4-hydroxyphenylpyruvate



3-phosphoserine

α-ketoglutarate

aminotransferase



phosphatase



CH2



COO–



tyrosine

aminotransferase



dehydrogenase



O2



CH2



CH2



homocysteine

methyltransferase

vit B12

THF

N5-methyl

THF



3-phospho

serine



COO-



H3+NCH



tyrosine



3-phospho

hydroxypyruvate



phosphoglycerate

mutase



Mg2+



COO–



OH



O2



CH2OPO32–

3-phosphoglycerate



COO



NH3



glutamate



HCOH



α-ketoglutarate

glutamate



NADH+H+



H2O



+



α-ketoglutarate



NAD+



COO–



phenylalanine



COO

H3+NCH



biosynthesis of

nucleotides, creatine,

porphyrins, glutathione



tryptophan



CH2







phosphoglycerate

kinase



ATP



COO–



CH2 CH

COO–



(CH2)3

arginase



NH

C

+



NH2



NH2



arginine



Chart 47.1  Gluconeogenesis from amino acids.



Part 5  Amino acid metabolism



95



Disorders of amino acid metabolism



48



There is a very large body of literature on these rare inborn errors of amino

acid metabolism, which has often contributed to our understanding of

­normal metabolic processes. A few examples are listed below and/or are

indicated on Charts 48.1 and 48.2.



Phenylketonuria

This is an autosomal recessive disorder resulting from deficiency of phenylalanine monooxygenase (also known as phenylalanine hydroxylase, PAH) a­ ctivity.

Whereas the monooxygenase is usually directly involved, in 3% of cases the

disorder is due to impaired synthesis of its coenzyme, t­etrahydrobiopterin.

The branched-chain amino acids

isoleucine



valine



CH3

CH3CH2CHCH

+NH



Cytosol



CH3



COO-



CH3 CH



3



α-ketoglutarate



CH3 O

CH3CH2



CH



α-ketoglutarate



CH3CH2



α-ketoisocaproate



carnitine

shuttle



branched chain

α-ketoacid dehydrogenase

NADH+H



+



CH3 O

C



SCoA



α-methylbutyryl CoA

FAD



dehydrogenase



carnitine

shuttle

+



NAD



CoASH



CO



NADH+H



+



C



CH2 C



SCoA



isovaleryl CoA

FAD



dehydrogenase



FADH2



FADH2



O



Mitochondrion



(CH3)2C CH C SCoA

β-methylcrotonyl CoA

H2O



CO2

ATP



carboxylase



ADP+P



i



CH3CH



C C SCoA

tiglyl CoA



H2O



hydratase



OH CH3 O

CH3 CH C C SCoA

α-methyl-β-hydroxybutyryl CoA



-OOC



CH3 O



CH3 O

CH2



C



C



OH



CoASH



CH3 O



NADH+H+



CH2 C



O



CH3 O



CH3 C CH C SCoA

α-methylacetoacetyl CoA



NADH+H+



H2O

hydrolase



HC CH2 COOmethylmalonate

semialdehyde



CO2

CoASH



acetyl CoA

acyl transferase



SCoA



β-hydroxy-β-methylglutaryl CoA

(HMGCoA)

HMGCoA lyase



dehydrogenase



O CH3



CoASH



acetyl CoA



O

CH2 C



CH3



NAD+

dehydrogenase



SCoA



hydratase



OH

-OOC



β-hydroxyisobutyrate

NAD+



C



β-methylglutaconyl CoA

H2O



hydratase



CH2 CH C SCoA

β-hydroxyisobutyryl CoA



CH



CH3



SCoA



methylacrylyl CoA

H2O



O



CH2 C



β-hydroxyβ-methyl

glutaric

aciduria



dehydrogenase

NADH+H+



acetyl CoA



CH3CH2C SCoA

propionyl CoA

CO2

ATP



carboxylase



ADP+Pi



propionyl CoA

carboxylase

deficiency



racemase



vit B12 mutase



acetyl CoA

acetoacetyl CoA

thiolase



to Krebs cycle



β-ketoacyl-CoA transferase (not in liver)



succinate



Chart 48.2  Disorders of branched amino acid metabolism.



96



methylmalonic

aciduria



succinyl CoA



acetoacetyl CoA



Type I tyrosinaemia is an autosomal recessive disease due to a deficiency of

fumarylacetoacetase. This causes accumulation of toxic intermediates, in

particular fumarylacetoacetate, which causes DNA alkylation and tumour

formation, and succinylacetone, which is an inhibitor of porphobilinogen

synthase (see Chapter 57). Type I tyrosinaemia is described in Chapter 49.

Treatment of type I tyrosinaemia has been revolutionized using NTBC

(2‐(2‐nitro‐4‐trifluoro‐methylbenzoyl)‐1,3‐cyclohexanedione) to inhibit 4‐

hydroxy‐phenylpyruvate dioxygenase. Also, restriction of dietary phenylalanine and tyrosine is necessary.



Non‐ketotic hyperglycinaemia

This condition is due to deficiency of glycine cleavage enzyme and causes

accumulation of glycine in body fluids including the nervous system, where

it causes neurological symptoms. This is because glycine can function as a

neurotransmitter and potentiates the N‐methyl‐d‐aspartate (NMDA) receptor. Consequently, when glycine accumulates, neonates suffer feeding difficulties, myoclonic seizures, hypotonia and attacks of apnoea. In severe cases

they may die or suffer severe neurological disease. In milder forms, patients

survive with mental retardation without suffering the other features of the

early onset form of the disease. Glycine is an inhibitory neurotransmitter in

spinal cords. Finally, hyperglycinaemia can also occur during valproate

therapy.



Histidinaemia

This is an autosomal recessive disorder in which deficiency of histidase

causes an accumulation of histidine.



In this autosomal recessive disorder, deficiency of the branched‐chain α‐

ketoacid dehydrogenase complex causes accumulation of the branched‐

chain amino acids isoleucine, valine and leucine, and their corresponding

α‐ketoacids, α‐methylbutyrate, isobutyrate and isovalerate. These compounds smell like maple syrup, hence the name of this condition. However,

some clinicians liken the odour to fenugreek.



This condition is caused by deficiency of l‐methylmalonyl CoA mutase or by

vitamin B12 deficiency. Patients suffer lethargy, delayed psychomotor development, seizures and acute encephalopathy. Most die in infancy or childhood.



L-methylmalonyl CoA

acetyl CoA



This autosomal recessive condition is due to deficiency of homogentisate

1,2‐dioxygenase. Homogentisate accumulates and is excreted in the urine

where, under alkaline conditions, it can undergo oxidation and polymerization to form the black pigment alkapton.



Methylmalonic aciduria



D-methylmalonyl CoA



acetyl CoA



Alkaptonuria



Maple syrup urine disease



NAD+



O



Tyrosine is metabolized by tyrosinase in melanocytes to form the pigment,

melanin. Deficiency of tyrosinase results in albinism.



+



O



(CH3)2CH



SCoA



FAD



FADH2



NADH+H



2



isobutyryl CoA

dehydrogenase



branched chain

α-ketoacid dehydrogenase



CO



O



(CH3)2CH



+



NAD



CoASH



branched chain

α-ketoacid dehydrogenase



2



COO-



CH2 C



(CH3)2CH



α-ketoisovalerate



+



CH



O

COO-



C



(CH3)2CH



NAD



CO



2



branched-chain

amino acid

aminotransferase



glutamate



O

COO-



C



carnitine

shuttle



maple syrup

urine disease



3



α-ketoglutarate



Albinism



Type I tyrosinaemia



CH2 CH COO+NH



CH3 CH



branched-chain

amino acid

aminotransferase



glutamate



α-keto-β-methylvalerate



CoASH



CH3



CH COO+NH

3



branched-chain

amino acid

aminotransferase



glutamate



leucine



Because phenylalanine cannot be metabolized to tyrosine, it accumulates and is

transaminated to phenylpyruvate which is a ‘phenylketone’. Phenylketonuria is

described in Chapter 49.



acetoacetate



ß‐Hydroxy‐ß‐methylglutaric aciduria

ß‐Hydroxy‐ß‐methylglutaryl CoA lyase (3‐hydroxy‐3‐methylglutaryl CoA

lyase) deficiency is an autosomal recessive disorder of leucine catabolism

and ketogenesis that is associated with hypoketotic hypoglycaemia, hyperammonaemia and metabolic acidosis (see Reye‐like syndrome, Chapter 58).



Metabolism at a Glance, Fourth Edition. J. G. Salway. © 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.



CH2 CH



COO



CH2 C



+



COO-



phenylpyruvate



tetrahydrobiopterin



O2

H2O



dihydrobiopterin



phenylketonuria

CH2 CH



COO



ATP



NADP+

dihydrobiopterin

reductase

NADPH+H+



4-monooxygenase



HCOH

CH2OPO32–

3-phosphoglycerate



Cytosol







glutamate



α-ketoglutarate

glutamate



4-hydroxyphenylpyruvate

O2



C



CO2



NADH+H+



alkaptonuria

H2O



isomerase



COO-



H2C COO–

malate



fumarase



fumarylacetoacetate



CH2

phosphoenolpyruvate



alanine

aminotransferase



CH3



H3+NCH



NH4+



3-sulphinylpyruvate



Cytosol



spontaneous



O



NADH+H+



NH4+



pyruvate



picolinate



spontaneous



NAD+



aminotransferase



glutamate



dehydrogenase



2-aminomuconate

NADH+H+



O





OOC(CH2)3 C COO–

α-ketoadipate



deaminase



2-aminomuconate

semialdehyde

NADH+H+



α-ketoglutarate



homoserine



H2O

NH4+



CO2



dehydrogenase



2-aminoadipate



H2O

cystathionase



cysteine



NAD+ and NADP+

synthesis



picolinate

carboxylase



NAD+

NADH+H+



cystathionine



dehydratase



3,4-dioxygenase



2-amino-3-carboxymuconate

semialdehyde



2 aminoadipate

semialdehyde



homocysteinuria



H2O



threonine



glutamate



COO



serine



CH3



O2



saccharopine dehydrogenase

(both mono- and bifunctional)

glutamate



cystathionine synthase



CHOH



α-ketoglutarate



SO32– H2O



adenosyl

homocysteinase



kynureninase



3-hydroxyanthranilate



H2O



homocysteine



COO–



H2O



H2O

alanine



saccharopine



adenosine



CH3



alanine



fumarylacetoacetase



H2O



H2O



3-hydroxykynurenine



H2O



NAD+



3-monooxygenase

(outer mitochondrial

membrane)



NADP+



lysine-α-ketoglutarate

reductase (bifunctional)



NADP+



methyl

transferase



S-adenosylhomocysteine



aminotransferase







C



dehydratase



dioxygenase



cysteine sulphinate



pyruvate

kinase

Mg2+ K+



ATP

α-ketoglutarate

glutamate



H3+NCH



CHOH



O2



COPO32–



ADP



COO-



cysteine



NADPH+H+



S-adenosylmethionine



THF



O2

NADPH+H+



α-ketoglutarate



adenosyl

transferase



methyl group

transferred to

acceptor



serine



SH



ATP

Pi+PPi



kynurenine



This pathway probably occurs in

both the cytosol and mitochondrion



H2O



formamidase



HCOO–



lysine



CH3



CH2OH



H2O



NH3



methionine



2,3-dioxygenase



N-formylkynurenine



CH2



+



S



Salvage

pathway



serine

hydroxymethyl

transferase







H3+NCH



CH2



COO–



phosphoenolpyruvate

carboxykinase



malate

dehydrogenase



NAD+



4-maleylacetoacetate



H2O



O



H2C COO–

oxaloacetate



homogentisate

O2

1,2 dioxygenase



CO2



GDP



N5,N10-methylene

THF



COO



H3+ NCH



enolase

Mg2+



H2O

GTP



COO–



NTBC



dioxygenase



CH2OH

2-phosphoglycerate



aspartate

aminotransferase



glycine



Pi



COO–



CH2



THF



COO–

H3+NCH2



phosphatase



HCOPO32-



succinylacetone



tyrosine

aminotransferase



vit B12



N5-methyl

THF



3-phospho

serine



3-phosphoserine

α-ketoglutarate

aminotransferase



COO-



melanin



tyrosinase deficiency

in albinism



tyrosine



α-ketoglutarate



3-phospho

hydroxypyruvate



dehydrogenase



phosphoglycerate

Mg2+ mutase



NH3



OH



α-ketoglutarate

glutamate



NADH+H+



H2O



+



tyrosinase



NAD+



COO–



CH2



CH2



homocysteine

methyltransferase



O2



CH2



H3+NCH



biosynthesis of

nucleotides, creatine,

porphyrins, glutathione



tryptophan



CH2



COO–



phosphoglycerate

kinase



NH3



NH



H3+NCH

1,3-bisphosphoglycerate



phenylalanine



+



COO–



NH3



ADP



COO–



CH2 CH



glycolysis



O





reductase



NAD+



NH4+



α-ketobutyrate



fumarate

dicarboxylate

carrier



tyrosinaemia I



pyruvate

carrier



acetoacetate



NADH+H+



C



malate

dehydrogenase



malate







FADH2



C SCoA



CoA



aspartate

CH2COO–



succinyl CoA

synthetase



CH2COO–



CH2



succinate



CoASH GTP



GDP+Pi



COO–

H2 NCH



/ 2 O2

2H+ H O



Mitochondrion



2



ADP



CH2

CONH2



asparagine

CH2COO–



isocitrate

dehydrogenase

Mg2+

CO2



CH2



NAD(P)H+H+

glutamate dehydrogenase

NAD(P)+



F1



CH2COO



NH4+



H2O



glutamate



CO2







OOC



CH2



methylmalonic

aciduria



ornithine

transcarbamoylase







urea

cycle



carbamoyl

phosphate



F0



C



CH3



C



SCoA



C



C



C



H O

SCoA



H2O



OH



O



CH3



CH CH2 C SCoA

3-hydroxybutyryl CoA



O



+

N

H2



COO–



NADP+



proline



NAD+



spontaneous



NADPH

H+



glutamate

γ-semialdehyde

glutamate

aminotransferase

α-ketoglutarate



glutamate

γ-semialdehyde

dehydrogenase



NADH

H+



CH2COO–

CH2



H3+N CH

H COO–



P5C synthetase

ADP

Pi



NADP+



NADPH ATP

H+



CH2 CH

N



NH



+NH



COO

3



histidine



histidase



H2O



urocanate



hydratase



H2O



THF



glutamate

formiminotransferase



lyase



3



(CH2)3



FIGLU

4-imidazolone5-propionate imidazoline (N-formiminoglutamate)

propionase



fumarate



C SCoA

2

H trans-Δ -enoyl-CoA



C CH2 C SCoA

acetoacetyl CoA



OH

CH3(CH2)12



C



H3C C SCoA

acetyl CoA



O

CH2



C



SCoA



H L-3-hydroxyacyl CoA

L-3-hydroxyacyl CoA

dehydrogenase



NAD+

NADH+H+



O

CH3(CH2)12



O



C CH2 C SCoA

3-ketoacyl CoA



O



CoASH

thiolase



H2O



CH3(CH2)12



C



CoASH



SCoA



thiolase



myristoyl CoA

O

H3C C SCoA

acetyl CoA



β-oxidation

β-oxidation



COO–



NH2



urea



AMP+PP

i



ar

argininosuccinate



H3+NCH



ornithine

N5-formimino-THF



NH4+







COOH +NCH



glutamate



ornithine



histidinaemia



ATP



C



O



O



aspartate

aspar

synthetase



C



enoyl-CoA

hydratase



NADH+H+



H3C C SCoA

acetyl CoA



pyrroline-5-carboxylate (P5C)



CH3(CH2)12



NAD+



dehydrogenase



SCoA



O

reductase



SCoA



CO2



hydratase



CH3



FAD



FADH2



glutaconyl CoA



H crotonyl CoA



O



OOCCH2CH2 C



SCoA



FAD



acyl-CoA

dehydrogenase



H O



succinyl CoA



FADH2



C



spontaneous



mutase (vitamin B12)



Pi



FAD

FADH2



H



L-methylmalonyl CoA



2ATP 2ADP+P

i



CH2 CH2 C

palmitoyl CoA



H O





OOCCH C



CH3(CH2)12



CH3



NAD+



citrulline



SCoA



acyl-CoA

dehydrogenase



carboxylase



O



glycine cleavage enzyme

deficiency (non-ketotic

hyperglycinaemia)



CO2



O



C



glutaryl CoA



racemase



IV



C



proline oxygenase



OOC(CH2)3



CH3 O



N5,N10-methylene

THF



NADH+H+



O







SCoA



OOCCH C SCoA

D-methylmalonyl CoA



NADH+H+



carbamoyl phosphate

synthetase

HCO3–



C



propionyl CoA

carboxylase

deficiency



THF







HOCH COO–

isocitrate



α-ketoglutarate

dehydrogenase



glycine cleavage

enzyme



+

NADH+H

NH +

4



HC COO–



O C COO–

O C SCoA

CO2 NADH NAD+ CoASH α-ketoglutarate

succinyl CoA

H+



ATP



1



H2O



[cis-aconitate]



+



COO



ADP+Pi



THF



aconitase



synthetase

CH2

AMP+PPi

– ATP



CH2COO–



serine

e

hydroxymethyll

transferase



+

NAD

H2O



O



ATP



NAD+



CO2



propionyl CoA



serine



aconitase



citrate



glutamate



H2 NCH



FAD



COO–



H2C COO–



NADH+H+



CH3CH2



N5,N10-methylene

THF



serine-pyruvate

aminotransferase



pyruvate



H2O



+



succinate

dehydrogenase



alanine



CH2COO–

HOC



citrate

synthase



COO– glutamine



OOCCH

fumarate



3-hydroxypyruvate



aspartate

aminotransferase



α-ketoglutarate



HCCOO





glutamate



fumarase



H2O



O



H2C COO– H O

2

oxaloacetate



glycine



dehydrogenase



NADH+H+



acetyl CoA



COO–



CHOH

H2C COO–



glycerate



CoASH

α-ketoadipate

dehydrogenase



NAD+



CO2



ATP



NADH+H+



O

H3C



NAD+



kinase



NAD+



HCO3–



COO–



ADP



pyruvate dehydrogenase



CO2



ADP+Pi



oxidized by

extrahepatic tissues



NAD+



thiamine PP

lipoate

riboflavin



pyruvate carboxylase

(biotin)



CoASH

α-ketoadipate

dehydrogenase



2-phosphoglycerate



CoASH

ATP



(CH2)3

NH



arginase



C



NH2



+



NH2



arginine



Chart 48.1  Disorders of amino acid metabolism.



Part 5  Amino acid metabolism



97



Phenylalanine and tyrosine metabolism



49



Phenylalanine can be hydroxylated to: (i) tyrosine, which is the precursor

of the pigment melanin; (ii) the thyroid hormones thyroxine (T4) and tri‐­

iodothyronine (T3); and (iii) the catecholamines dopamine, noradrenaline

and adrenaline. Any additional phenylalanine or tyrosine surplus to requirement for protein synthesis will be oxidized to acetoacetate and fumarate.



Tyrosinaemia III



Inborn errors of phenylalanine metabolism

Phenylketonuria (PKU)



This is a rare autosomal dominant disorder caused by a partial defect of

4‑hydroxyphenylpyruvate oxidase activity. This partial defect prevents the

epoxide intermediates produced during the reaction from rearranging to form

homogentisate and instead they react with glutathione to form hawkinsin

(which is an amino acid named after the Hawkins family in which the disorder

was discovered). Infants present with metabolic acidosis, a body odour ‘like a

swimming pool’ and excrete hawkinsin. They also excrete 5‐oxoproline (pyroglutamic acid), presumably secondary to glutathione depletion (see Chapter 15).

In later life, they excrete 4‐hydroxycyclohexylacetic acid (4‐HCAA).



This autosomal recessive disorder, the most common inborn error of

amino acid metabolism in the UK, is caused by deficiency of phenylala‑

nine monooxygenase (also known as phenylalanine hydroxylase,

PAH). Usually the monooxygenase is directly involved but in 3% of cases

the disorder is due to impaired synthesis of its coenzyme, tetrahydrobi‑

opterin. In both cases, because phenylalanine cannot be metabolized to

tyrosine, it accumulates and is transaminated to the phenylketone,

phenylpyruvate.

PKU patients not treated with a phenylalanine‐free diet suffer neurological symptoms and have a low IQ. There are two hypotheses to explain this:

1 The toxic metabolite hypothesis. Phenylpyruvate and its metabolite

­phenyllactate can inhibit metabolic processes. However, they do so only at

concentrations greater than those found in PKU patients.

2 The transport hypothesis. This proposes that high concentrations of

­phenylalanine competitively interfere with the transport into the brain

of other large neutral amino acids including tryptophan (a precursor of

­serotonin, see Chapter  50), and tyrosine (a precursor of dopamine,

Chart 49.1).



Inborn errors of tyrosine metabolism

Tyrosinaemia I (hepatorenal tyrosinaemia)



This is an autosomal recessive disorder of fumarylacetoacetase. Patients

suffer severe liver disease and develop carcinoma caused by accumulation of

the toxic, electrophilic metabolites, fumarylacetoacetate and succinylace‑

tone (Chart  49.1). Succinylacetone can also cause porphyria‐like attacks

because it is a competitive inhibitor of porphobilinogen synthase (see

Chapter 57). Because oxidation of tyrosine is inhibited, tyrosine is diverted

towards the catecholamines which are produced in increased amounts and

may cause hypertension. Patients also develop hypermethioninaemia and

have a ‘cabbage‐like’ odour.

Traditionally, type I tyrosinaemia was treated with low‐tyrosine and low‐

tryptophan diets and liver transplantation. However, since 1991 a trial of the

4‐hydroxyphenylpyruvate oxidase inhibitor, NTBC (2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione), plus dietary restriction of tryptophan and tyrosine, has been conducted with great success.

NTBC is a weed killer that, during toxicity trials (for its herbicidal use),

caused hypertyrosinaemia in experimental animals. It was shown to inhibit

4‐hydroxyphenylpyruvate oxidase. Then, following inspired and bold lateral

thinking (and no doubt much trepidation at the thought of using a weed

killer as a therapeutic drug), it was given to children with tyrosinaemia I,

with remarkable results. NTBC stopped the production of fumarylacetoacetate and succinylacetone, thereby preventing the severe liver damage

caused by these hepatotoxins. This clinical trial was successful and in 2002

the US Food and Drug Administration approved the use of NTBC.



Tyrosinaemia II (Richner–Hanhart syndrome;

oculocutaneous tyrosinaemia)



This is an autosomal recessive disorder of tyrosine aminotransferase that

affects the eyes, skin and central nervous system. The eye problems are due

to accumulation of tyrosine in the cornea. Once diagnosed, this condition is

successfully treated and the lesions are reversed with low dietary tyrosine

and phenylalanine formulations.



98



This is a very rare autosomal recessive disorder caused by deficiency of 4‐

hydroxyphenylpyruvate oxidase. Tyrosine and phenolic metabolites accumulate and patients suffer neurological symptoms and mental retardation.



Hawkinsinuria



Other inborn errors of tyrosine metabolism



Albinism and alkaptonuria are described in Chapter 48.



Parkinson’s disease

This disease, which usually develops from age 60 onwards, is caused by

destruction of the brain region, known as the substantia nigra, that produces

the neurotransmitter dopamine. The symptoms of Parkinson’s disease

include tremor, muscular rigidity and akinesia. The use of the dopamine precursor l‐DOPA (levodopa) was a landmark in the treatment of Parkinson’s

disease, and was subsequently refined by combining it with a peripheral (i.e.

extracerebral) l‐DOPA decarboxylase inhibitor (e.g. carbidopa or benserazide). Other therapeutic drugs used are dopamine agonists and the catechol‐

O‐methyltransferase (COMT) inhibitors entacapone and tolcapone, which

prevent the catabolism of l‐DOPA to form 3‐O‐methyldopa (3‐OMD).



Phaeochromocytoma

This rare condition is usually caused by a tumour of the adrenal medulla, which

produces excessive amounts of the catecholamines adrenaline (epinephrine)

and noradrenaline (norepinephrine), and their catabolic products metadrena‑

line (metepinephrine), normetadrenaline (normetepinephrine) and vanillylmandelic acid (VMA; also known as hydroxymethoxymandelic acid (HMMA)).

However, 10% of cases occur in the sympathetic nerve chain and overproduce

noradrenaline. If the tumour releases a surge of catecholamines, patients suffer a

hypertensive attack associated with severe headache, sweating, palpitations, anxiety, glucosuria and, if adrenaline predominates, tachycardia. The tumour can be

surgically removed but handling of the tumour during the operation can cause a

surge of catecholamines, precipitating a hypertensive crisis. Patients are therefore

prepared preoperatively with adrenergic blockers. There are reports that treatment with α‐methyl‐p‐tyrosine, which inhibits tyrosine 3‐monooxygenase,

has been used to deplete the tumour of catecholamines prior to the operation.



Neuroblastoma

This rare tumour usually presents in children less than 5 years old and 70% have

metastatic disease at diagnosis. During the last decade, mass screening trials of

children were conducted, the outcome of which remains controversial. Urine

was dried onto filter paper and used for assays of homovanillic acid (HVA) and

VMA, which are excreted in increased amounts in neuroblastoma.



Dopamine and mental illness

The ‘dopamine hypothesis’ for schizophrenia postulates increased brain

dopaminergic activity. Although several research approaches suggest an

association of psychosis with altered dopaminergic transmission, the evidence is not conclusive. The COMT gene is receiving special attention as a

candidate risk factor for schizophrenia.



Metabolism at a Glance, Fourth Edition. J. G. Salway. © 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.



+



COO-



CH2 CH

+NH



3



COO- +

NADH+H



CH2 C



α-ketoglutarate

glutamate



NH4



OH



O

+



NAD



CO

2



phenylpyruvate



phenyllactate



phenylacetate



OH

OH



4 3



O



2



4-monooxygenase

H O

2



1 2



CH



HO

+



CH2NH3



dihydrobiopterin

reductase



dihydrobiopterin



phenylketonuria



HO



NADP+



NADPH+H



CH



1 2



HO



+



S-adenosyl

methionine



CH2NH3



S-adenosyl

homocysteine



H2O



H2O2



O2



oxidation



CH



CHO

3-methoxy4-hydroxy

mandelicaldehyde



+



NH4



+NH



reduction



3



CH2 CH



OCH3



4 3



monoamine

oxidase

(MAO)



noradrenaline



+



OH



OCH3



4 3



catecholO-methyltransferase

(COMT)



1 2



tetrahydrobiopterin



H2O



monoamine oxidase

(MAO)



OH



aminotransferase



phenylalanine



O2

H2O2



CH2COO-



COO-



CH2 CH



thyroid hormones

T4, T3



COO-



normetadrenaline



OH

4 3



measured in urine

in phaeochromocytoma



1 2

OH



OH



CH2



tyrosine



+



albinism



α-ketoglutarate



COO-



CH2 CH

+NH



tyrosinase



3



HO



tyrosine

3-monooxygenase



dihydrobiopterin

reductase

NADPH+H+



O

DOPA quinone



dihydrobiopterin







OCH3



4 3



catecholO-methyltransferase

(COMT)



1 2



CH



HO CH

S-adenosyl

CH2OH

methionine

3-methoxy-4-hydroxy

3,4-dihydroxy phenylglycol

mandelic acid

(DOPEG)

(MOPEG)

S-adenosyl

homocysteine

reduction

CH2OH



O2



tetrahydrobiopterin



NADP+



O



tyrosine

aminotransferase



1 2







tyrosine



melanin



Cu2+



tyrosinaemia II



COO



OH

OH



4 3



CHNH3



α-methylp-tyrosine



H2 O

CH2 C



glutamate



OH



COO-



catecholO-methyltransferase

(COMT)



OCH3



O







CH2

+



CHNH3



OH

4-hydroxyphenylpyruvate



O2



– NTBC







O



CH2



O



CH2



O

CH2 CH



S-adenosyl

homocysteine



H

N



C



CH2NH3



O

epoxide



OH

epoxide



CH2



glutathione

S-transferase



C

CH2



H3+N



CH COO-



glutathione

O



CH2



COOS



O



CH2 CH



C



H

N



O2



OH



COO-



CH2



COO-



HO



CH2



(4-HCAA)



catechol-O-methyltransferase

(COMT)



S-adenosylhomocysteine

OH



CH COO-



glutamate



O



CH2



COOS



O



CH2 CH C



H

N



+



cysteinyl

glycinase



in alkaptonuria a

black quinone

polymer is formed



+



NADP



S



O



CH2 CH C

+



H

N



COOCH2



OH



hawkinsin



COO-



H



C



H



C C



CH2 C



CH2



+



CH2NH3



C



H



H



C



C



2H



CH2 C



CH2



COO-



O

O

fumarylacetoacetate



COO-



COO-



CH2



CH2



CH2

C



C



CH2



CH2



CH2



C



O



fumarate

acetoacetate

oxidized by

extrahepatic tissues



Krebs cycle

(Chapter 19)



succinyl acetone



CH2



monoamine

oxidase

(MAO)



H2O

+



CH2NH3



3-methoxytyramine



O2



OH



H2O2

+



NH4



oxidation



OCH3



OH



OCH3



CH2



CH2



CHO



COOH



HVA



Neuroblastoma

Urinary excretion

of HVA is increased

COOCH2

CH2

C



tyrosinaemia I



OCH3



homovanillic acid



O



CH3



OH



S-adenosyl

homocysteine



CH2

O



COOsuccinyl

acetate



H2O



fumarylacetoacetate

hydrolase



S-adenosyl

methionine



dopamine



isomerase



-OOC



catecholO-methyltransferase

(COMT)



OH



CH2



COO-



O

O

4-maleylacetoacetate



NH3



(2-L-cystein-S-yl-1,4dihydroxycyclohex-5-en-1-yl)



CH3



alkaptonuria



1,2 dioxygenase



+



COO-



NH



OH



O2



reductase

CH2



CH

CH2



adrenaline



CH2



glycine



HO



HO

OH



COO+



H3N



OH



1 2



OH



homogentisate



OH



4 3



CH2 COO-



COOCH2



NH3



NADPH + H



vanillylmandelic acid



(measured in urine in

phaeochromocytoma

and neuroblastoma)



S-adenosylmethionine



CH2



3



VMA



COO-



CH2

H +N



COO–



(measured in urine in

phaeochromocytoma)



noradrenaline



COO-



CH



CH

+



OH

4-hydroxycyclohexyl

acetic acid



OCH3



OH



CH2NH3



O



H3+N CH



γ-glutamyltranspeptidase



HO



CH3



dihydroascorbate



CH2



CH2



NH



metadrenaline

OH



3



1 2



CH

CH2



S-adenosyl

homocysteine



H2O



NH

C



4



1 2



HO

S-adenosyl

methionine



OCH3



4 3



catecholO-methyltransferase

(COMT)



dopamine

β-monooxygenase



hawkinsinuria

rearrangement of the

epoxides is inhibited

in Hawkinsinuria



O



CH2



OH



OH

+



NH



COO–

3,4-dihydroxy

mandelic acid



catechol-O-methyltransferase

(COMT)



dopamine



HS



CH



S-adenosyl

methionine



ascorbate

COO-



HO



CHO

3,4-dihydroxy

mandelic aldehyde



CH2



COO-



oxidation



CH



OH



carbidopa and

benserazide



COO-



1 2



CO2

OH



OH



4 3



1 2



HO



L-DOPA decarboxylase



dihydroascorbate



OH

OH



4 3



COO–

dihydroxyphenylalanine

(L-DOPA)



4-hydroxyphenylpyruvate oxidase



CO2



monoamine

oxidase

(MAO)



OH



S-adenosyl CH2

+

methionine

CHNH3



entacapone

and tolcapone



COO–

3-O-methyldopa

(3-OMD)



ascorbate



tyrosinaemia III



S-adenosyl

homocysteine



OH



OH



O



CH2

N+H3



5-aminolevulinic acid (ALA)

Succinylacetone is formed in tyrosinaemia I.

This has structural similarities to

5-aminolevulinic acid and competitively

inhibits PBG synthase causing porphyria-like

symptoms (Chart 57.1)



Chart 49.1  Phenylalanine and tyrosine metabolism.



Part 5  Amino acid metabolism



99



Tryptophan metabolism: the biosynthesis of NAD+, serotonin

and melatonin



50



Chart 50.1  (opposite) Tryptophan

metabolism.



Hartnup disease, niacin deficiency and pellagra

Tryptophan is an essential amino acid whose importance is demonstrated in

Hartnup disease. This is an autosomal recessive disorder in which renal loss

and intestinal malabsorption of tryptophan and other neutral amino acids

occurs. Patients with Hartnup disease suffer neurological symptoms and skin

lesions resembling severe sunburn, which are similar to pellagra. Pellagra is

classically seen in dietary niacin deficiency, niacin being the ­collective term for

the NAD+ precursors nicotinic acid and nicotinamide. However, tryptophan

metabolism via the kynurenine pathway also ­produces precursors of NAD+.



Kynurenine pathway

The regulatory enzymes for the kynurenine pathway are tryptophan 2,3‐

dioxygenase (TDO) and the less specific indoleamine 2,3‐dioxygenase

(IDO) (Chart 50.1).



Production of NAD+ and NADP+



The kynurenine pathway is the main pathway for tryptophan metabolism and it

provides precursors that supplement dietary niacin (i.e. nicotinic acid and nicotinamide) for the biosynthesis of NAD+ and NADP+. It is generally accepted that

60 mg of tryptophan is equivalent to 1 mg of niacin. Because kynureninase needs

vitamin B6, deficiency of the latter can cause secondary pellagra. In a malnourished population with marginally sufficient dietary tryptophan, women of

childbearing age are twice as vulnerable as men to suffer pellagra. This is because

oestrogens inhibit several enzymes of the kynurenine pathway that produce the

precursors of NAD+. Conversely, when tryptophan is abundant, any surplus to

requirement is metabolized via α‐ketoadipate to acetyl CoA for oxidation in

Krebs cycle and ATP p

­ roduction by oxidative phosphorylation.



Kynurenine and its metabolites prevent maternal rejection

of the fetus



Upstream products of the kynurenine pathway may have several important

functions, for example, in immunology and regulation of cell proliferation,

and the pathway is attracting attention as a target for the development of

new drugs. Work in mice suggests that placental trophoblasts express IDO,

which is involved in feto‐maternal tolerance. The production of kynurenine,

picolinate and quinolinate prevent maternal T cells from activating a lethal

anti‐fetal response, and they may also have antimicrobial functions.



Indoleamine pathway for the formation of serotonin

(5‑hydroxytryptamine) and melatonin

A pathway of major neuroendocrinological importance is the indoleamine

pathway, which makes the neurotransmitter serotonin and the hormone

melatonin in the pineal gland and retina (Chart  50.1). Because impaired

serotonin metabolism has been associated with the ‘affective disorders’ (disorders of mood), this pathway has been a target for the treatment of depression. Indeed, tryptophan and 5‐hydroxytryptophan have historically been

used to treat depression. Also, melatonin has been associated with seasonal

affective disorder (SAD) but this remains unproven. This depression is

thought to be caused by the long, dark nights of winter. Many sufferers benefit from light treatment by exposure to 2500 lux for 2 hours each morning.



Depression as a neurochemical disease



Although one in four people experience mental disease, it is a sad fact that

sufferers are frequently stigmatized, even in the 21st century, because of the

debilitating effect it has on their personalities. All too frequently depression is

unfairly considered to be self‐indulgent weakness due to lack of resolve and

determination. This is despite the fact that a psychiatric condition such as

endogenous depression is a disease with a substantial biochemical

­component. Perhaps it is time to refer to these disorders as ‘neurochemical diseases’ to prevent the stigmatizing effect that ‘mental illness’ can have on people.

Of course, not all depression is primarily of neurochemical origin. For

example, bad news such as failing exams or bereavement will quite naturally

cause a period of ‘reactive’ depression secondary to the tragic event.



100



However, there are people with a happy, contented lifestyle who for no

apparent reason slip into a period of inconsolable depression. It is these people who are probably suffering from an ‘endogenous’ biochemical failure to

make sufficient brain serotonin and consequently their brain function is

depressed. Clearly, lack of space here permits only a simplistic view of reactive and endogenous depression since it is likely there is an interaction

between the two. However, there is an urgent need for an enlightened public

attitude to these ‘taboo’ diseases.

The indoleamine‐amine hypothesis for affective disease proposes that

brain concentrations of neuroactive amines, e.g. serotonin, are associated

with mood disorders. In depression, there is insufficient serotonin present

for neurotransmission so brain function is depressed. Successful treatment of

depression with serotonin reuptake inhibitors such as Prozac, which increase

synaptic concentrations of serotonin, supports this hypothesis. Conversely, it

is hypothesized that excessive concentrations of serotonin cause mania.



Serotonin metabolism

The regulatory enzyme for serotonin biosynthesis is tryptophan hydroxylase.

Note that tryptophan hydroxylase has to compete for tryptophan with its rivals

TDO and IDO. It is possible that if the hydroxylase is insufficiently active, brain

concentrations of serotonin would be depleted and cause depression.

Catabolism of serotonin occurs when it is deaminated by monoamine oxidase and then oxidized to 5‐hydroxyindoleacetic acid (5‐HIAA). 5‐HIAA is

excreted in excessive amounts in patients with carcinoid syndrome.



Melatonin metabolism

Melatonin is made from its precursor serotonin in the pineal gland ­normally

during periods of darkness. Melatonin is almost totally absent in daylight.

The regulatory enzyme is arylalkylamine N‐acetyltransferase (AANAT).

AANAT is up‐regulated by noradrenergic stimulation that normally occurs

during the dark phase of the day. It is down‐regulated by light, which stimulates photoreceptors in the retina and initiates signals that are transmitted

through a neural circuit including the suprachiasmatic nuclei (SCN, also

called the ‘biological clock’) and then onwards towards the pineal gland.

NB: During continuous darkness melatonin v­ aries up and down, driven by

the SCN, i.e. a light/dark cycle is not needed to produce a rhythm.



Melatonin biosynthesis: AANAT is up‐regulated in the dark

by noradrenaline



Noradrenergic stimulation of primarily β‐ but also α‐adrenergic receptors

on pinealocytes and retinal photoreceptors activates protein kinase A

(PKA) which phosphorylates and activates AANAT (Chart  50.1).

Phosphorylated AANAT is now protected from degradation by binding to

its ‘bodyguard’ 14‐3‐3 protein (named after the laboratory number of the

fraction from which it was isolated by its discoverers).



Melatonin biosynthesis: AANAT is down‐regulated by light



Light, via the SCN, adjusts the time duration of sympathetic input to the

pineal which inhibits synthesis of melatonin in the pineal gland. Light causes

a rapid decrease in both the activity of AANAT and the amount of AANAT

protein, which has a t1/2 of 3 minutes. When noradrenergic stimulation

ceases, PKA activity also decreases, and protein phosphatase dephosphorylates AANAT which loses its protective 14‐3‐3 protein and is exposed to and

destroyed by proteosomal proteolysis.



Catabolism of melatonin



Melatonin is hydrophobic and must be conjugated with hydrophilic groups

before it can be excreted in the urine. It is metabolized by CYP 1A2 to 6‐

hydroxymelatonin, which can be conjugated in two ways. The principal

excretory product is 6‐sulphatoxymelatonin with the sulphate donated

by  3′‐phosphoadenosine‐5′‐phosphosulphate (PAPS). Alternatively, it

forms 6‐hydroxymelatonin glucuronide.



Metabolism at a Glance, Fourth Edition. J. G. Salway. © 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.



Hartnup

disease

nerve ending

Hartnup disease.

Defective renal tubular

reabsorption of neutral

amino acids results in

urinary loss of tryptophan



tryptophan



C CH2 CH COO+NH

3

N

H CHO

H O

2



COO-



O



kynurenine

O

2

+

NADPH+H



xanthurenate excreted

in urine after

tryptophan load in

vitamin B6 deficiency



3-monooxygenase

(outer mitochondrial

membrane)



NADP+



O

COO-



+

N

H

dietary

nicotinate

(niacin)



alanine



HO



AKAP



CHO

-OOC



phosphoribosylpyrophosphate



CHO

-OOC



NH2



spontaneous



CO



2



H2O



+

N



NADH+H



PPi



H2O



-OOC (CH )

2 3



H O

2



+

NH4



COO-



cystathionase



N

N



O





O



CH2

O



P



+

N



O



O





O



O



O

C NH2



N

N



O

H H



SCoA



nicotinamide adenine

dinucleotide



CH3



HO OH

nicotinamide adenine

dinucleotide



O







CH2

O



P



glutaconyl CoA



C



SCoA



CO2







C



O



OH OH



O



NH2

N



CH2



N



O



ADP



H H



SO2–

cysteine

sulphinate







P



C



O

spontaneous



CH2



pyruvate



SO2–



3-sulphinylpyruvate



SO32–

sulphite



H2O



O2



SCoA



CH3



N

N



O





deaminase



O



O







O

nicotinamide adenine dinucleotide phosphate



(NADP+)



O



melatonin



sulphate



to mitochondrion



ATP



O2

NADPH+H



ATP sulphurylase



PPi



HO



H2O



O



+NH



CH2 CH2



NADH+H+



N



O2, H2O

O

O



+

NH4 , H2O2







HC



O-



S



O P



O



O



C



N



CH2



O



O



H2O



SCoA



O-



2 acetyl CoA



NAD



+



aldehyde

dehydrogenase



mitochondrion



O



H H



C







O OH



H



O-



HO



P

O





CH2 COO

N

H



CH2 CH2





SO4



NH



N

H



5-hydroxyindoleacetic acid



(5-HIAA)



6-sulphatoxymelatonin



H



H



OH



H

O



UDP



UDP



O



CH3 O



O

OH



UDP-glucuronyl

transferase



3´-phosphoadenosine5´-phosphate



NADH



O-



H



UDP glucuronate



3´-phosphoadenosine-5´-phosphosulphate

(PAPS)



arylsulphotransferase



+

2H



5-HIAA

excreted in

urine in

carcinoid

syndrome



O





CH2 CHO

N

H



N

H

6-hydroxymelatonin



N









HO



CH3



C



NH



HO



CH



C



CH2 CH2







H H



2CoASH



N



C



+



O



CH3 O



NH2



+



H2O



AMPS kinase



monoamine

oxidase



C CH2 C SCoA

acetoacetyl CoA



NADP



ATP



(serotonin)



NAD+



cytochrome P-450

(CYP1A2)



adenosine 5´-phosphosulphate

(AMPS)



3



N

H

5-hydroxytryptamine (5-HT)



O



H3C C







S

O



crotonyl CoA



O



O



CH3



suphite oxidase

deficiency



HO



O



C



aminotransferase



α-ketobutyrate



H H



HO

O



C



NH4+



thiolase



H



P



C



O



O

O



CH

CH2



cysteine

dioxygenase



COO–



COO

α-ketoglutarate

glutamate



H2O2



C



hydratase



O



O



H 3N



+



homoserine



CH CH2 C SCoA

3-hydroxybutyryl CoA



C NH2



melatonin



taurine



FADH2



H



dehydrogenase



+

N



CH3



SO3–







dietary

cysteine



CH3



(NAD+)



C



N

H



conjugated with bile

acids (Chapter 43)



CH2



hypotaurine



FAD



C



OH



N



kinase



CH2



pyrophosphorylase



H H



ATP



-OOC



H



N



(NAD+)



C



PPi



NH2



CH2



-OOC(CH )

2 3



ATP



OH OH



O



O



spontaneous



nicotinamide mononucleotide



H



P



CH



cysteine



H O



H2O



SO2–



COO

O2



CH2



oxidase



H O



nicotinamide

phosphoribosyl

transferase



HO OH

nicotinate adenine

dinucleotide



CH2







NADH+H+



CO2



acyl-CoA

dehydrogenase



phosphoribosylpyrophosphate



NAD+

synthetase



+



SH

NAD+



glutaryl CoA



+

N

H

dietary

nicotinamide

(niacin)



H H



glutamate

ADP



2



decarboxylase



H2O



CoASH

α-ketoadipate

dehydrogenase



NH2

N



CH2 CH2 NH



NH3+

O2



CH2



CO



cystathionine



CH2



C NH2



hydroxyindole –O –

methyltransferase

(HIOMT)

S-adenosyl-



homocysteine



NH3+



cystathionine

synthase

Vit Bb



H2O



H3N



O



O



CH3 O



CH3



homocysteine



urine



H



C



NH



S-adenosylmethionine



COO



OH OH



ATP

glutamine



14-3-3

protein



adenosyl

homocysteinase



α-ketoadipate



+

N



O



O



H H



Pi



S-adenosylhomocysteine



serine



C



CH2 CH2



methyl

transferase



adenosine



O



COO-



N



AANAT

A

(i

(inactive)

e)



protein

phosphatase



14-3-3

protein



S-adenosylmethionine



pyrophosphorylase



O



AANAT

(active)



N

H

N-acetyl-5-hydroxytryptamine



H2O

adenosyl

transferase



ATP

P +PP

i

i



homocysteine



NH2



methionine



ATP



O



ADP



P



arylalkylamine

N-acetyltransferase

(AANAT)







OH OH

nicotinate mononucleotide



CH2



arylalkylamine

N-acetyltransferase

(AANAT)

ATP



O



homocysteine

methyltransferase



+



2-aminomuconate



H



O



protein

synthesis



THF



methionine salvage

pathway

(Chapter 54)



NADH+H+

hydratase and

dehydrogenase

NAD+



+

N COOH

picolinate



O



P



AANAT

A which

is not bound

to 14–3–3

pproteins is

destroyed

y byy

pproteosomal

proteolysis



3



CoASH



CO2



2-aminomuconate semialdehyde



COO-



O



R



O



(serotonin)



NAD+

decarboxylase



COO-



+

N COOH

quinolinate







+NH



CH2 CH2



CH3 C SCoA



3



N

H

5-hydroxytryptamine (5-HT)



(vitamin B12)



decarboxylase



COO-



CH2



HO



HO



CO2



O



R



AKAP



NH2



H O

2



P



active

protein kinase A



cyclic

AMP



N

H

5-hydroxytryptamine (5-HT)



+NH



CH2 CH2



N 5-methyl THF



CHO

-OOC



spontaneous



O



R



dietary

methionine



2-amino-3-carboxymuconate

semialdehyde



O



C



R



COO-



PPi







C



aromatic L-amino acid

decarboxylase



3,4-dioxygenase



phosphoribosylpyrophosphate

nicotinate

phosphoribosyl

transferase



O-3POCH2



dihydrobiopterin

reductase

+

NADPH+H



dihydrobiopterin



(serotonin)



Kynurenine

pathway



NH2

OH

3-hydroxyanthranilate

O2



quinolinate

phosphoribosyl

transferase

PPi



tryptophan

hydroxylase



CO2



COO-



3



COO-



vitamin B6



kynureninase



CH3 CH COO+NH



amino acids



NADP+



vitamin B6



H2O



inactive cyclic

cyc

y lic AMP

phosphodiesterase-3B



O2

tetrahydrobiopterin



CH2 CH COO+NH

N

3

H

5-hydroxytryptophan



OH

3-hydroxykynurenine



xanthurenate



cyclic AMP



AMP



HO



C CH2 CH COO+NH

3

NH2



Pinealocytes and

retinal photoreceptros



PP

i



ATP



H2O



Indoleamine

pathway



H2O



OH

+

N

OH H



extra

hepatic

tissue

including

pineal



ubiquitous,

very active

in intestine



C CH2 CH

+NH

3

NH2



adenylate

cyclase



3



NH



·



GS



COO-



tryptophan



indoleamine

O22,3-dioxygenase

superoxide

(IDO)

anion radical



formamidase



formate



CH2 CH

+NH



molecular

oxygen

O2



tryptophan

2,3-dioxygenase

(TDO)



N-formylkynurenine



HCOO-



to folate cycle



noradrenaline

receptor



liver



O



cytosol



noradrenaline



γ-glutamyl

cycle



plasma membrane



nocturnal stimulation of nerve releases noradrenaline

which increases melatonin concentrations



C



CH3

H

HO



O



CH3 O

COO



CH2 CH2







O

H

OH



H



H



OH



O

H



NH



C



CH3



N

H



6-hydroxymelatonin glucuronide



Part 5  Amino acid metabolism



101



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Chart 45.1: formation of alanine and glutamine by muscle

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