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3 Myogenesis: The Development and Regeneration of Muscle
4. CELLULAR AND MOLECULAR MECHANISMS OF PROTEIN SYNTHESIS AMONG TISSUES
FIGURE 4.5 The role of muscle regulatory factors in satellite cell response to injury and growth factors. The satellite cell may leave the
quiescent state, proliferating and differentiating into active myoblasts, capable of repairing myofiber damage and contributing to hypertrophy.
The satellite cell lineage is maintained via divergence from myoblast formation and restoration of the quiescent state (not to scale).
skeletal muscle stem cells (ie, satellite cells) continue to proliferate, relocating between the basal lamina of the
myofiber and the sarcolemma which envelops it (Schultz and McCormick, 1994). These juvenile satellite cells
eventually serve a functional role in muscle growth, as they transition to become adult, mitotically quiescent
satellite cells, the primary source of myoblasts required for muscle repair and regeneration (Relaix and
Zammit, 2012; Yin et al., 2013).
The activation of satellite cells occurs in response to several of the same exogenous and endogenous stimuli
that upregulate mTORC1 signaling. For example, satellite cells are activated in response to muscle damage,
which can occur following vigorous exercise (Fig. 4.5). Muscle injury causes satellite cells to mobilize and migrate
to the site of tissue damage (Sanes, 2003). Satellite cells can also be activated by hypertrophic stimulants and an
increase in circulating growth factors, including IGF-1, vascular endothelial growth factor (VEGF), and fibroblast
growth factor (FGF) (Ceafalan et al., 2014).
Once activated, several regulatory factors are necessary to assist satellite cells during myogenesis (Tajbakhsh,
2009). These include myogenic regulator factors (MRFs), notably the paired-box (Pax) transcription factors Pax3
and Pax7, which are expressed in adult satellite cells and have both distinct and overlapping functions in MRF
regulation (Relaix et al., 2006). Pax3 and Pax7 act to modulate myogenic progenitor cells and regulate their
differentiation, as well as the expression of downstream transcription factors, leading to a net increase in
myogenic transcription initiation and increased protein synthesis. They are also necessary for cell specificity
during development, particularly Pax3, which is required for embryonic myogenesis (Messina et al., 2009).
The exact mechanisms for how Pax3 and Pax7 regulate satellite cell biogenesis, survival, and self-renewal
remain elusive. It appears that they serve as the master regulators of myogenesis and regeneration, orchestrating
the involvement of other important MRFs to control the commitment of satellite cells to myoblast formation and
differentiation, and the fusion of myocytes to myofibers; these important MRFs include MyoD, myogenic factor
5 (Myf5), Myf6, and myogenin (Khan et al., 1999; Olguin and Pisconti, 2012; Olguin et al., 2007; Rudnicki and
Jaenisch, 1995; Seale et al., 2004).
The earliest markers of myogenic cells are Myf5 and MyoD, which are involved in the commitment
of proliferating satellite cells to myogenesis and regeneration (Rudnicki et al., 1993). These two MRFs appear to
have somewhat redundant functionality, as knocking out either of these genes still allows for myogenesis and
regeneration, albeit at limited capacity (Rudnicki et al., 1993). If both genes are silenced, however, myocyte
formation does not occur.
MyoD has been shown to regulate cell cycling and the ability of the satellite cell to move from G1 to the
S phase of mitosis (Zhang et al., 2010). Following mitotic division, satellite cell progeny undergo divergent fates
(Fig. 4.5). Decreased Pax7 expression and associated increases in MyoD expression drive differentiation, leading
to increased expression of myogenin. This cascade results in increased protein synthesis, and associated muscle
growth and repair, via terminal differentiation, whereby the myocytes are either fused with an existing myofiber
or join with other myocytes to form a new myofiber (Olguin and Pisconti, 2012). Alternatively, satellite cell
I. GENERAL AND INTRODUCTORY ASPECTS
progeny can maintain Pax7 expression and suppress MyoD and myogenin (Zammit et al., 2004). This pathway
allows for continuance of the myogenic lineage, renewing the quiescent satellite cell pool. Maintenance of satellite
cells provides for future myogenesis in response to exercise or muscle injury.
4.4. APPLIED IMPLICATIONS OF PROTEIN SYNTHESIS IN VIVO
The highly regulated processes of protein synthesis are critical for the maintenance of human health and life.
Protein synthesis can be positively impacted by exercise, both aerobic and resistive, and nutrition, meaning
sufficient energy and amino acid intakes to meet metabolic demand. In the case of muscle protein, disuse and/or
denervation can lead to atrophy, with rates of proteolysis exceeding dramatically reduced protein synthesis.
Certain disease states—including sepsis, cancer, and uremia—are also associated with diminished protein
synthesis, upregulated proteolysis, and overall degradation of muscle protein.
Similarly, dietary energy and protein deficiencies can deprive the body of the building blocks needed to
generate new proteins. Decreased whole body protein synthesis can have serious consequences on health and
longevity. Diminished hepatic protein synthesis can lead to impaired plasma protein concentrations which may
manifest as edema and ascites. In the case of plasma transporters, movement of hydrophobic compounds
through the aqueous blood becomes diminished if transporter protein synthesis is impaired. This can severely
impact the transport of fat-soluble vitamins and plasma lipids, as well as interfere with correct dosing of
hydrophobic pharmaceuticals. Similarly, decreased antibody and immune factor production increases susceptibility to infection. Diminished enzyme and protein hormone synthesis can have system-wide implications and,
depending on the severity and duration of these limitations, can drive increased mortality. It is these deficiencies
of protein synthesis, and their associated outcomes, that illustrate the critical importance of proper regulation
and maintenance of protein synthesis.
4.5. CONCLUSIONS AND SUMMARY OF KEY POINTS
As described within this chapter:
• protein synthesis is a highly regulated process essential for life;
• polypeptides are created, based on an mRNA code, through the process of translation, requiring multiple
initiation and elongation factors working in concert with the ribosome and amino acid-charged tRNA;
• mTORC1 is the primary regulator of protein synthesis, sensitive to multiple upstream effectors and working
through various downstream factors to modulate ribosomal activity;
• satellite cells serve a key role in regulating muscle protein synthesis in order to maintain, repair, and augment
myofibers and myocytes;
• impairment of protein synthesis can result in severe physiological manifestations that may increase the risk of
morbidity and mortality.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as
official or as reflecting the views of the US Army or Department of Defense. Any citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement of approval
of the products or services of these organizations. The authors have no potential conflicts of interest to report.
Baar, K., Esser, K., 1999. Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise.
Am. J. Physiol. 276, C120À127.
Bar-Peled, L., Schweitzer, L.D., Zoncu, R., Sabatini, D.M., 2012. Ragulator is a GEF for the rag GTPases that signal amino acid levels to
mTORC1. Cell 150, 1196À1208.
Bentzinger, C.F., Wang, Y.X., Rudnicki, M.A., 2012. Building muscle: molecular regulation of myogenesis. Cold Spring Harb. Perspect. Biol. 4.
I. GENERAL AND INTRODUCTORY ASPECTS
4. CELLULAR AND MOLECULAR MECHANISMS OF PROTEIN SYNTHESIS AMONG TISSUES
Beugnet, A., Tee, A.R., Taylor, P.M., Proud, C.G., 2003. Regulation of targets of mTOR (mammalian target of rapamycin) signalling by
intracellular amino acid availability. Biochem. J. 372, 555À566.
Bolster, D.R., Crozier, S.J., Kimball, S.R., Jefferson, L.S., 2002. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle
through down-regulated mammalian target of rapamycin (mTOR) signaling. J. Biol. Chem. 277, 23977À23980.
Bolster, D.R., Jefferson, L.S., Kimball, S.R., 2004. Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-,
amino acid- and exercise-induced signalling. Proc. Nutr. Soc. 63, 351À356.
Burd, N.A., Holwerda, A.M., Selby, K.C., West, D.W., Staples, A.W., Cain, N.E., et al., 2010a. Resistance exercise volume affects myofibrillar
protein synthesis and anabolic signalling molecule phosphorylation in young men. J. Physiol. 588, 3119À3130.
Burd, N.A., West, D.W., Staples, A.W., Atherton, P.J., Baker, J.M., Moore, D.R., et al., 2010b. Low-load high volume resistance exercise
stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men. PLoS One 5, e12033.
Burd, N.A., Andrews, R.J., West, D.W., Little, J.P., Cochran, A.J., Hector, A.J., et al., 2012. Muscle time under tension during resistance exercise
stimulates differential muscle protein sub-fractional synthetic responses in men. J. Physiol. 590, 351À362.
Carbone, J.W., McClung, J.P., Pasiakos, S.M., 2012. Skeletal muscle responses to negative energy balance: effects of dietary protein. Adv. Nutr.
Ceafalan, L.C., Popescu, B.O., Hinescu, M.E., 2014. Cellular players in skeletal muscle regeneration. Biomed. Res. Int. 2014, 957014.
Cesena, T.I., Cui, T.X., Piwien-Pilipuk, G., Kaplani, J., Calinescu, A.A., Huo, J.S., et al., 2007. Multiple mechanisms of growth
hormone-regulated gene transcription. Mol. Genet. Metab. 90, 126À133.
Cuthbertson, D.J., Babraj, J., Smith, K., Wilkes, E., Fedele, M.J., Esser, K., et al., 2006. Anabolic signaling and protein synthesis in human
skeletal muscle after dynamic shortening or lengthening exercise. Am. J. Physiol. Endocrinol. Metab. 290, E731À738.
Devlin, R.B., Emerson Jr., C.P., 1978. Coordinate regulation of contractile protein synthesis during myoblast differentiation. Cell 13, 599À611.
Drummond, M.J., Rasmussen, B.B., 2008. Leucine-enriched nutrients and the regulation of mammalian target of rapamycin signalling and
human skeletal muscle protein synthesis. Curr. Opin. Clin. Nutr. Metab. Care 11, 222À226.
Drummond, M.J., Dreyer, H.C., Fry, C.S., Glynn, E.L., Rasmussen, B.B., 2009. Nutritional and contractile regulation of human skeletal muscle
protein synthesis and mTORC1 signaling. J. Appl. Physiol. 106, 1374À1384.
Hoffer, L.J., Taveroff, A., Robitaille, L., Hamadeh, M.J., Mamer, O.A., 1997. Effects of leucine on whole body leucine, valine, and threonine
metabolism in humans. Am. J. Physiol. 272, E1037À1042.
Inoki, K., Li, Y., Zhu, T., Wu, J., Guan, K.L., 2002. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.
Nat. Cell Biol. 4, 648À657.
Ivanova, N.B., Dimos, J.T., Schaniel, C., Hackney, J.A., Moore, K.A., Lemischka, I.R., 2002. A stem cell molecular signature. Science 298, 601À604.
Jiang, W., Zhu, Z., Thompson, H.J., 2008a. Dietary energy restriction modulates the activity of AMP-activated protein kinase, Akt, and
mammalian target of rapamycin in mammary carcinomas, mammary gland, and liver. Cancer Res. 68, 5492À5499.
Jiang, W., Zhu, Z., Thompson, H.J., 2008b. Modulation of the activities of AMP-activated protein kinase, protein kinase B, and mammalian
target of rapamycin by limiting energy availability with 2-deoxyglucose. Mol. Carcinog. 47, 616À628.
Khan, J., Bittner, M.L., Saal, L.H., Teichmann, U., Azorsa, D.O., Gooden, G.C., et al., 1999. cDNA microarrays detect activation of a myogenic
transcription program by the PAX3-FKHR fusion oncogene. Proc. Natl. Acad. Sci. U.S.A. 96, 13264À13269.
Kim, I.Y., Schutzler, S., Schrader, A., Spencer, H., Kortebein, P., Deutz, N.E., et al., 2015. Quantity of dietary protein intake, but not pattern of
intake, affects net protein balance primarily through differences in protein synthesis in older adults. Am. J. Physiol. Endocrinol. Metab.
Kimball, S.R., 2014. Integration of signals generated by nutrients, hormones, and exercise in skeletal muscle. Am. J. Clin. Nutr. 99, 237SÀ242S.
Kimball, S.R., Farrell, P.A., Jefferson, L.S., 2002. Invited review: role of insulin in translational control of protein synthesis in skeletal muscle by
amino acids or exercise. J. Appl. Physiol. (1985) 93, 1168À1180.
Laplante, M., Sabatini, D.M., 2009. mTOR signaling at a glance. J. Cell Sci. 122, 3589À3594.
Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., Avruch, J., 2005. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702À713.
Ma, X.M., Blenis, J., 2009. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307À318.
Magnuson, B., Ekim, B., Fingar, D.C., 2012. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks.
Biochem. J. 441, 1À21.
Mascher, H., Andersson, H., Nilsson, P.A., Ekblom, B., Blomstrand, E., 2007. Changes in signalling pathways regulating protein synthesis in
human muscle in the recovery period after endurance exercise. Acta Physiol. (Oxf) 191, 67À75.
Messina, G., Sirabella, D., Monteverde, S., Galvez, B.G., Tonlorenzi, R., Schnapp, E., et al., 2009. Skeletal muscle differentiation of embryonic
mesoangioblasts requires pax3 activity. Stem Cells 27, 157À164.
Mitchell, C.J., Churchward-Venne, T.A., West, D.D., Burd, N.A., Breen, L., Baker, S.K., et al., 2012. Resistance exercise load does not determine
training-mediated hypertrophic gains in young men. J. Appl. Physiol. 113, 71À77.
Moore, D.R., Robinson, M.J., Fry, J.L., Tang, J.E., Glover, E.I., Wilkinson, S.B., et al., 2009. Ingested protein dose response of muscle and
albumin protein synthesis after resistance exercise in young men. Am. J. Clin. Nutr. 89, 161À168.
Murgas Torrazza, R., Suryawan, A., Gazzaneo, M.C., Orellana, R.A., Frank, J.W., Nguyen, H.V., et al., 2010. Leucine supplementation of
a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent
translation initiation. J. Nutr. 140, 2145À2152.
Nair, K.S., Schwartz, R.G., Welle, S., 1992. Leucine as a regulator of whole body and skeletal muscle protein metabolism in humans.
Am. J. Physiol. 263, E928À934.
Nobukuni, T., Joaquin, M., Roccio, M., Dann, S.G., Kim, S.Y., Gulati, P., et al., 2005. Amino acids mediate mTOR/raptor signaling through
activation of class 3 phosphatidylinositol 3OH-kinase. Proc. Natl. Acad. Sci. U.S.A. 102, 14238À14243.
Olguin, H.C., Pisconti, A., 2012. Marking the tempo for myogenesis: Pax7 and the regulation of muscle stem cell fate decisions. J. Cell Mol.
Med. 16, 1013À1025.
Olguin, H.C., Yang, Z., Tapscott, S.J., Olwin, B.B., 2007. Reciprocal inhibition between Pax7 and muscle regulatory factors modulates myogenic
cell fate determination. J. Cell Biol. 177, 769À779.
I. GENERAL AND INTRODUCTORY ASPECTS
Pasiakos, S.M., 2012. Exercise and amino acid anabolic cell signaling and the regulation of skeletal muscle mass. Nutrients 4, 740À758.
Pasiakos, S.M., McClung, J.P., 2011. Supplemental dietary leucine and the skeletal muscle anabolic response to essential amino acids.
Nutr. Rev. 69, 550À557.
Pasiakos, S.M., McClung, H.L., McClung, J.P., Margolis, L.M., Andersen, N.E., Cloutier, G.J., et al., 2011. Leucine-enriched essential amino acid
supplementation during moderate steady state exercise enhances postexercise muscle protein synthesis. Am. J. Clin. Nutr. 94, 809À818.
Potter, C.J., Pedraza, L.G., Xu, T., 2002. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4, 658À665.
Proud, C.G., 2007. Amino acids and mTOR signalling in anabolic function. Biochem. Soc. Trans. 35, 1187À1190.
Relaix, F., Zammit, P.S., 2012. Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage.
Development 139, 2845À2856.
Relaix, F., Montarras, D., Zaffran, S., Gayraud-Morel, B., Rocancourt, D., Tajbakhsh, S., et al., 2006. Pax3 and Pax7 have distinct and
overlapping functions in adult muscle progenitor cells. J. Cell Biol. 172, 91À102.
Roux, P.P., Ballif, B.A., Anjum, R., Gygi, S.P., Blenis, J., 2004. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous
sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. U.S.A. 101, 13489À13494.
Rudnicki, M.A., Jaenisch, R., 1995. The MyoD family of transcription factors and skeletal myogenesis. Bioessays 17, 203À209.
Rudnicki, M.A., Schnegelsberg, P.N., Stead, R.H., Braun, T., Arnold, H.H., Jaenisch, R., 1993. MyoD or Myf-5 is required for the formation of
skeletal muscle. Cell 75, 1351À1359.
Sakamoto, K., Arnolds, D.E., Ekberg, I., Thorell, A., Goodyear, L.J., 2004. Exercise regulates Akt and glycogen synthase kinase-3 activities in
human skeletal muscle. Biochem. Biophys. Res. Commun. 319, 419À425.
Sancak, Y., Sabatini, D.M., 2009. Rag proteins regulate amino-acid-induced mTORC1 signalling. Biochem. Soc. Trans. 37, 289À290.
Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar-Peled, L., et al., 2008. The Rag GTPases bind raptor and mediate
amino acid signaling to mTORC1. Science 320, 1496À1501.
Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A.L., Nada, S., Sabatini, D.M., 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal
surface and is necessary for its activation by amino acids. Cell 141, 290À303.
Sanes, J.R., 2003. The basement membrane/basal lamina of skeletal muscle. J. Biol. Chem. 278, 12601À12604.
Schultz, E., McCormick, K.M., 1994. Skeletal muscle satellite cells. Rev. Physiol. Biochem. Pharmacol. 123, 213À257.
Seale, P., Ishibashi, J., Scime, A., Rudnicki, M.A., 2004. Pax7 is necessary and sufficient for the myogenic specification of CD45 1 :Sca1 1 stem
cells from injured muscle. PLoS Biol. 2, E130.
Sheffield-Moore, M., Yeckel, C.W., Volpi, E., Wolf, S.E., Morio, B., Chinkes, D.L., et al., 2004. Postexercise protein metabolism in older and
younger men following moderate-intensity aerobic exercise. Am. J. Physiol. Endocrinol. Metab. 287, E513À522.
Shepstone, T.N., Tang, J.E., Dallaire, S., Schuenke, M.D., Staron, R.S., Phillips, S.M., 2005. Short-term high- vs. low-velocity isokinetic
lengthening training results in greater hypertrophy of the elbow flexors in young men. J. Appl. Physiol. 98, 1768À1776.
Smith, E.M., Finn, S.G., Tee, A.R., Browne, G.J., Proud, C.G., 2005. The tuberous sclerosis protein TSC2 is not required for the regulation of the
mammalian target of rapamycin by amino acids and certain cellular stresses. J. Biol. Chem. 280, 18717À18727.
Tajbakhsh, S., 2009. Skeletal muscle stem cells in developmental versus regenerative myogenesis. J. Intern. Med. 266, 372À389.
Tavares, M.R., Pavan, I.C., Amaral, C.L., Meneguello, L., Luchessi, A.D., Simabuco, F.M., 2015. The S6Kprotein family in health and disease.
Life Sci. 131, 1À10.
Tipton, K.D., Ferrando, A.A., Williams, B.D., Wolfe, R.R., 1996. Muscle protein metabolism in female swimmers after a combination of
resistance and endurance exercise. J. Appl. Physiol. (1985) 81, 2034À2038.
Tyagi, R., Shahani, N., Gorgen, L., Ferretti, M., Pryor, W., Chen, P.Y., et al., 2015. Rheb inhibits protein synthesis by activating the
PERK-eIF2alpha signaling cascade. Cell Rep. S2211-1247, 00027-0003.
Wang, X., Li, W., Williams, M., Terada, N., Alessi, D.R., Proud, C.G., 2001. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6
kinase. EMBO J. 20, 4370À4379.
White, J.P., Gao, S., Puppa, M.J., Sato, S., Welle, S.L., Carson, J.A., 2013. Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal
muscle. Mol. Cell Endocrinol. 365, 174À186.
Yin, H., Price, F., Rudnicki, M.A., 2013. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23À67.
Zammit, P.S., Golding, J.P., Nagata, Y., Hudon, V., Partridge, T.A., Beauchamp, J.R., 2004. Muscle satellite cells adopt divergent fates:
a mechanism for self-renewal? J. Cell Biol. 166, 347À357.
Zhang, K., Sha, J., Harter, M.L., 2010. Activation of Cdc6 by MyoD is associated with the expansion of quiescent myogenic satellite cells.
J. Cell Biol. 188, 39À48.
I. GENERAL AND INTRODUCTORY ASPECTS
C H A P T E R
Role of Amino Acid Transporters
in Protein Metabolism
P. M. Taylor
Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee,
Sir James Black Centre, Dundee, United Kingdom
5.1. AMINO ACID TRANSPORTERS: STRUCTURE AND MOLECULAR FUNCTION
Proteolipid cell membranes act as selective barriers to polar solutes such as amino acids (AAs) and sugars
(Stein, 1986). As AAs do not readily diffuse across lipid membranes, membrane-spanning protein “pores” are
needed to help move (or “transport”) AA between the cytosol and extracellular fluid and also between
membrane-bound compartments of cells, for example, cytosol and endosomal lumen (see Broer, 2008; Forrest
et al., 2011 for review). AA transporter proteins form such pores and act as “gatekeepers” to permit selective AA
transport across intracellular and plasma membranes. There are six major families of AA transporters in the
Solute Carrier (SLC) gene superfamily (SLC1,6,7,36,38,43 families), an “orphan” SLC16 (monocarboxylate family)
transporter, which transports aromatic AA, and three SLC families (SLC17,25,32), which include AA transporters
expressed only on intracellular membranes (see Tables 5.1 and 5.2; note that a subset of transporters localize to
both endosomal and plasma membranes). The protein products of these transporter genes are characterized by
having a primary protein structure with multiple (typically 10À12) stretches of hydrophobic AA (Fig. 5.1A).
Within the membrane, these hydrophobic regions are arranged into a series of transmembrane helices (TMH)
which typically fold themselves into two (or more) distinct opposed or intertwined domains organized around a
central “pore” translocation pathway (Fig. 5.1B). A relatively small number of underlying protein folds have been
recognized across seemingly disparate solute transporter gene families (see Forrest et al., 2011 for review).
The SLC3 gene family, although classed as AA transporters, are single TMH glycoproteins acting as regulatory
subunits for the glycoprotein-associated amino acid transporter/heteromeric amino acid transporter subfamily of
SLC7 transporters (see Table 5.1). There are also a group of 7-TMH AA transporter proteins from the LCT
(lysosomal cystine transporter) gene family expressed at the lysosomal membrane (Je´ze´gou et al., 2012; Zhai
et al., 2001) (see Table 5.2).
Transporters (or “carriers”) function essentially in similar ways to enzymes, except that they catalyze a vectorial movement of substrate across the membrane rather than a chemical reaction converting substrate to
product. Both types of catalytic mechanism are describable using principles of energetics in terms of the freeenergy of different conformational states and the energy barriers between them (see Forrest et al., 2011 for
review). A generally accepted “alternate access” model of transport involves a catalytic cycle in which sequential conformational changes “switch” the transporter protein between states in which the substrate binding site
(or “binding center”) is open to one or other side of the membrane (see Fig. 5.1C). This conformational switch
is achieved by movement of the opposing transmembrane domains of the protein, which swivel or “rock”
about the binding center (the “rocker-switch” mechanism). For most AA transporters, this does not require
a significant movement of the actual binding center, which remains located near the center of the membrane
(in cross-section). Secondary “gates” may regulate accessibility of the bound substrate to free solution
The Molecular Nutrition of Amino Acids and Proteins.
© 2016 Elsevier Inc. All rights reserved.
5. ROLE OF AMINO ACID TRANSPORTERS IN PROTEIN METABOLISM
TABLE 5.1 Amino acid transporters of plasma membranes
AA transporter family
(see Fig. 5.1)
SLC6A1, A11, A13
Excitatory AA transporters
(i) Cationic AA transporters
(ii) Glycoprotein-associated AA
Aromatic AA, TH T
Pro, Gly, Ala,
Gln, Asn, His
Proton-coupled AA transporters
Small neutral AA transporters
Large neutral AA transporters
Only AA transporters with human orthologues are included.
Na1-dependent NAA antiport, exact mechanism uncertain.
The gpaATs form heteromeric transporters with an “accessory” SLC3 (8.A.9) subunit, either SLC3A1 (rBAT/NBAT) or SLC3A2 (F42hc/CD98).
Primarily Na1-NAA/CAA antiport.
First column shows transporter families as classified by Human Genome Organisation (HGNC), see http://www.bioparadigms.org, and (in parentheses) by the
International Union of Biochemistry and Molecular Biology (IUBMB), see http://www.tcdb.org. See also, for example, Broer and Palacin (2011); Hediger et al.
(2013); Schioăth et al. (2013); for original sources and further details on substrate ranges and tissue expression.
AAA, anionic AA; (L/S)NAA, (large/small) neutral AA; CAA, cationic AA; TH, thyroid hormone.
I. GENERAL AND INTRODUCTORY ASPECTS