Endogenous Metabolic Modulators: Emerging Therapeutic Potential of Amino Acids

Overview

Journal iScience

Publisher Cell Press

Date 2020 Oct 26

PMID 33103071

Citations 7

Authors

Michael J Hamill

Raffi Afeyan

Manu V Chakravarthy

Tony Tramontin

Affiliations

Soon will be listed here.

Abstract

Multifactorial disease pathophysiology is complex and incompletely addressed by existing targeted pharmacotherapies. Amino acids (AAs) and related metabolites and precursors are a class of endogenous metabolic modulators (EMMs) that have diverse biological functions and, thus, have been explored for decades as potential multifactorial disease treatments. Here, we review the literature on this class of EMMs in disease treatment, with a focus on the emerging clinical studies on AAs and related metabolites and precursors as single- and combination-agents targeted to a single biology. These clinical research insights, in addition to increasing understanding of disease metabolic profiles and combinatorial therapeutic design principles, highlight an opportunity to develop EMM compositions with AAs and related metabolites and precursors to target multifactorial disease biology. EMM compositions are uniquely designed to enable a comprehensive approach, with potential to simultaneously and safely target pathways underlying multifactorial diseases and to regulate biological processes that promote overall health.

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References

Nicholson J, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W . Host-gut microbiota metabolic interactions. Science. 2012; 336(6086):1262-7. DOI: 10.1126/science.1223813. View

Niihara Y, Miller S, Kanter J, Lanzkron S, Smith W, Hsu L . A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. 2018; 379(3):226-235. DOI: 10.1056/NEJMoa1715971. View

Dreyer H, Owen E, Strycker L, Smolkowski K, Muyskens J, Kirkpatrick T . Essential Amino Acid Supplementation Mitigates Muscle Atrophy After Total Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial. JB JS Open Access. 2018; 3(2):e0006. PMC: 6145559. DOI: 10.2106/JBJS.OA.18.00006. View

Campollo O, Sprengers D, McIntyre N . The BCAA/AAA ratio of plasma amino acids in three different groups of cirrhotics. Rev Invest Clin. 1992; 44(4):513-8. View

Badoud F, Lam K, DiBattista A, Perreault M, Zulyniak M, Cattrysse B . Serum and adipose tissue amino acid homeostasis in the metabolically healthy obese. J Proteome Res. 2014; 13(7):3455-66. DOI: 10.1021/pr500416v. View

Mardinoglu A, Bjornson E, Zhang C, Klevstig M, Soderlund S, Stahlman M . Personal model-assisted identification of NAD and glutathione metabolism as intervention target in NAFLD. Mol Syst Biol. 2017; 13(3):916. PMC: 5371732. DOI: 10.15252/msb.20167422. View

Li T, Geng L, Chen X, Miskowiec M, Li X, Dong B . Branched-chain amino acids alleviate nonalcoholic steatohepatitis in rats. Appl Physiol Nutr Metab. 2013; 38(8):836-43. DOI: 10.1139/apnm-2012-0496. View

Husted A, Trauelsen M, Rudenko O, Hjorth S, Schwartz T . GPCR-Mediated Signaling of Metabolites. Cell Metab. 2017; 25(4):777-796. DOI: 10.1016/j.cmet.2017.03.008. View

Mardinoglu A, Boren J, Smith U, Uhlen M, Nielsen J . Systems biology in hepatology: approaches and applications. Nat Rev Gastroenterol Hepatol. 2018; 15(6):365-377. DOI: 10.1038/s41575-018-0007-8. View

10.

Brenner B, Meyer T, Hostetter T . Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982; 307(11):652-9. DOI: 10.1056/NEJM198209093071104. View

11.

Hasin Y, Seldin M, Lusis A . Multi-omics approaches to disease. Genome Biol. 2017; 18(1):83. PMC: 5418815. DOI: 10.1186/s13059-017-1215-1. View

12.

Kinny-Koster B, Bartels M, Becker S, Scholz M, Thiery J, Ceglarek U . Plasma Amino Acid Concentrations Predict Mortality in Patients with End-Stage Liver Disease. PLoS One. 2016; 11(7):e0159205. PMC: 4943589. DOI: 10.1371/journal.pone.0159205. View

13.

Ohara M, Ogawa K, Suda G, Kimura M, Maehara O, Shimazaki T . L-Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis. Hepatol Commun. 2018; 2(8):906-918. PMC: 6078216. DOI: 10.1002/hep4.1207. View

14.

Taegtmeyer H, Ingwall J . Creatine--a dispensable metabolite?. Circ Res. 2013; 112(6):878-80. PMC: 3646410. DOI: 10.1161/CIRCRESAHA.113.300974. View

15.

Guijas C, Montenegro-Burke J, Warth B, Spilker M, Siuzdak G . Metabolomics activity screening for identifying metabolites that modulate phenotype. Nat Biotechnol. 2018; 36(4):316-320. PMC: 5937131. DOI: 10.1038/nbt.4101. View

16.

Dillon E, Sheffield-Moore M, Paddon-Jones D, Gilkison C, Sanford A, Casperson S . Amino acid supplementation increases lean body mass, basal muscle protein synthesis, and insulin-like growth factor-I expression in older women. J Clin Endocrinol Metab. 2009; 94(5):1630-7. PMC: 2684480. DOI: 10.1210/jc.2008-1564. View

17.

Zhu J, Sova P, Xu Q, Dombek K, Xu E, Vu H . Stitching together multiple data dimensions reveals interacting metabolomic and transcriptomic networks that modulate cell regulation. PLoS Biol. 2012; 10(4):e1001301. PMC: 3317911. DOI: 10.1371/journal.pbio.1001301. View

18.

Cheng F, Kovacs I, Barabasi A . Network-based prediction of drug combinations. Nat Commun. 2019; 10(1):1197. PMC: 6416394. DOI: 10.1038/s41467-019-09186-x. View

19.

Honda T, Kobayashi Y, Togashi K, Hasegawa H, Iwasa M, Taguchi O . Associations among circulating branched-chain amino acids and tyrosine with muscle volume and glucose metabolism in individuals without diabetes. Nutrition. 2016; 32(5):531-8. DOI: 10.1016/j.nut.2015.11.003. View

20.

Broer S, Broer A . Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem J. 2017; 474(12):1935-1963. PMC: 5444488. DOI: 10.1042/BCJ20160822. View