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Department of Biomedical Chemistry, Institute of International Health, University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan
* To whom correspondence should be addressed. E-mail: k38takai{at}nyc.odn.ne.jp.
On the occasion of the "Transdisciplinary International Conference on Aromatic Amino Acids and Related Substances," the organizing committee honors and thanks the expert participants from many areas of aromatic amino acid (AAA)3 research. In this transdisciplinary meeting, "aromatic paradigms" were pursued in structural, molecular, information, and systems biology followed by papers on metabolism, pathology, and therapy in humans. Whereas basic biosciences invariably aim at coherent accounts of life as a highly complex yet united system, problem-oriented approaches like medicine and nutrition study other aspects of the same reality. This conference holds an exceptional raison de e'tre, because all paradigms cut across the unique axis of "aromaticity," eventually leading to a theoretical and experimental coherence. In 1991 K. Takai and 56 other scientists studying amino acids launched the first "Transdisciplinary International Conference on Amino Acid Research," and held the initial congress in Kyoto, Japan (1) under the sponsorship of Ajinomoto Co., Inc. In the past 5 y, subsequent conferences have been held for glutamine (2), arginine (3), and branched chain amino acids (BCAA) (4).
At the end of the last millennium, research on aromatic amino acids stepped into a newer stage. The cation-
interaction between the -face of aromatic amino acids and cations was shown to constitute the fourth major, noncovalent chemical force in nature, along with those by hydrophobic effect/hydrogen bonding/ion pairing. Recent structural biology based on X-ray analyses of membrane/cytosolic protein crystals, solution NMR studies, thermodynamics of ligand-binding/permeation processes, mutation analyses, and computer-based methods for 3D structures from the primary protein structure verified that the cation- interactions of electrostatic nature play crucial roles to support the macromolecular structure/recognition in life processes.
Professor Wüthrich, a Nobel Laureate of Chemistry in 2002, who was a charter member of the First International Congress on Amino Acid Research, facilitated Session 1, which focused on the chemistry and structural biology of AAA and related compounds. We have been grateful for his interest and attendance in our transdisciplinary conferences over the decades.
In Session 1, Dr. Dougherty described the nature of cation- interactions as a noncovalent, unique force between aromatic amino acids and cations, along with annotations of paradigms in protein-ligand interactions and protein secondary structure (5).
Dr. Tajkhorshid described cation- interactions in transmembrane water channels, the aquaporins (6). These transmembrane channels facilitate the selective transport and gating of water and other hydrophilic entities through the lipid bilayers in plasma membranes. In aquaporins, critical aromatic residues such as phenylalanine (Phe) and/or Phe/tryptophan (Trp) inside the channel are involved in gating of water molecules through the transmembrane channel.
Session 2 focused on AAA residues and signal transduction across biological hierarchies. Tyrosine (Tyr) kinases (TK) are central regulators of signaling pathways that control differentiation, transcription, cell cycle progression, apoptosis, motility, and invasion. Dr. Nagar described the search for specific protein TK inhibitors, an intense area of research because of the potential for drug development (7). For example, the TK c-Abl, whose normal mechanism of autoinhibition is disrupted in chronic myelogenous leukemia, is inactivated by the small-molecule inhibitor, Imatinib.
Dr. Conigrave described how aromatic L-amino acids activate the calcium-sensing receptors (CaR) that regulate whole-body calcium metabolism (8). The intracellular Ca2+ ion, defined by the influx/efflux through Ca2+ channels and binding proteins, serves as a unitary messenger for countless cellular functions. The CaR senses both the AAA and Ca2+ outside the cells and induces intracellular Ca2+ oscillation and exocytosis. This paradigm of corecognition of Ca2+ and AAA signals on the CaR molecule provides a cutting edge example of dual signaling pathways.
In the central nervous system, Tyr and Trp are converted to aromatic amine modulators such as dopamine, norepinephrine, and serotonin (5-hydroxytryptamine), which act via G protein-coupled receptors (GPCR). GPCR comprise a huge family of 
800 proteins with 7 transmembrane domains, but so far the X-ray crystal structure of this family has been determined only for bovine rhodopsin, which has a low homology to other GPCR. Dr. Goddard summarized his progress in computational methods for predicting the 3-dimensional structure of GPCR and for predicting the binding sites for various agonists and antagonists (9).
Dr. Fernstrom focused on Tyr and Phe as precursors for biosynthesis of catecholamines and on the metabolic perturbation of catecholamine metabolism by dietary loading or deprivation of precursor AAA in vivo (10). Because Tyr administration stimulates catecholamine synthesis in the brain, a number of functions such as blood pressure and the secretion of pituitary hormones have been examined.
In the second half of this transdisciplinary conference, Sessions 3 and 4 focused on the normal state and on perturbations due to diseases or to therapeutic outcomes. First, to reinforce our foundation in human studies, Dr. Matthews reviewed AAA kinetics with special reference to stable isotope techniques and stoichiometric balance of nutritional intake of Phe, an essential amino acid (11).
Dr. Endo described animal models of tyrosinemia (12). Mutations causing excessive accumulation of Tyr and Phe, such as tyrosinemia and phenylketonuria (PKU), involve the Phe hydroxylase (PAH)-catalyzed conversion of Phe to Tyr with the cofactor tetrahydrobiopterin (BH4). Mutations in the last enzyme of the Tyr catabolic pathway cause hereditary tyrosinemia type I with progressive liver damage, a high risk of hepatoma, and injury of renal tubular cells due to "aromatic toxicity." A diet low in Tyr/Phe is applied; otherwise, tyrosinemia patients die due to acute and chronic liver insufficiencies, but caspase inhibitors prevent apoptosis in the hereditary tyrosinemia type I patient.
PKU, known since 1934, is caused by defective activity of PAH, or, less frequently, dihydobiopterin reductase and, in rare cases, pyruvoyltetrahydrobiopterin synthetase due to recessive mutations. Dr. de Baulny reviewed the French national project for life-span care and epidemiological genetics of PKU (13). French guidelines have been established to specify the minimal diagnosis procedures and optimal treatment of patients.
Dr. Matalon described their work on the response of PKU to BH4 (14). BH4 is a cofactor to one of 400 mutant PAH with partial activity. Supplementation with the cofactor BH4 has been shown to decrease plasma Phe concentrations of some PKU patients.
Dr. Hyland described the clinical aspects of AAA metabolism in the brain. Insufficiencies of BH4 lead to concurrent deficits of 3 brain neuromodulators such as dopamine, norepinephrine, and 5-hydroxytryptamine, as well as to PKU (15). Treatment of BH4 deficiencies is designed to increase central neurotransmitter levels, to restore normal blood Phe if hyperphenylalaninemia is present, and to relieve other symptoms to various extents.
Session 4 dealt with AAA requirements and pathologies in humans. Dr. Pencharz reviewed the requirements of AAA in healthy humans (16). He described 3 studies that define the total AAA requirements using the Indicator Amino Acid Oxidation method.
Dr. Dejong described AAA metabolism in liver failure that is associated with hepatic encephalopathy (17). AAA such as Phe, Tyr, and Trp have been suggested to play a causal role in hepatic encephalopathy through their connection with BCAA, because the 2 subtypes of amino acids share the same transporter. After major liver resection, there was no change in the plasma BCAA/AAA ratio, whereas cirrhosis patients show lower ratios, of about 1/3, and plasma AAA levels were inversely correlated with residual liver volume. If the BCAA/AAA imbalance is confirmed in more severe liver failure in humans, modern treatment methods such as the molecular adsorbent recirculating system may be useful.
Dr. Kopple described AAA metabolism during chronic kidney disease (18). In contrast to rat kidney, the human kidney exhibits net uptake of Phe and net output of Tyr, due to the substantial activity of renal PAH. Thus, chronic renal failure is accompanied by impairment of the conversion of Phe to Tyr, resulting in a decrease in both plasma Tyr concentration and the Tyr/Phe ratio, with plasma Phe concentration staying unchanged, in distinct contrast to the massive increase of plasma Phe concentration in PKU.
Dr. Meadows presented a description of specific amino acid dependency that regulates the cellular behavior of melanoma (19). Restriction of specific amino acids induces mitochondria-initiated apoptosis in melanoma cells.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author disclosure: Travel expense to attend the meeting paid by Ajinomoto Company, Inc.
3 Abbreviations used: AAA, aromatic amino acid; BCAA, branched chain amino acid; BH4, tetrahydrobiopterin; CaR, Calcium-sensing receptor; GPCR, G protein-coupled receptor; PAH, phenylalanine hydroxylase; Phe, phenylalanine; PKU, phenylketonuria; TK, tyrosine kinase; Trp, tryptophan; Tyr, tyrosine.
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LITERATURE CITED |
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 TOP LITERATURE CITED |
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1. Takai K, editor. Frontiers and new horizons in amino acid research. Amsterdam: Elsevier; 1992. pp. 1–705.
2. Wilmore DW, Rombeau JL, editors. Glutamine metabolism: nutritional and clinical significance. J Nutr. 2001;131 (Suppl 9):2447S–602S.
3. Morris SM Jr, Loscalzo J, Bier DM, Souba WW, editors. Arginine metabolisms: enzymology, nutrition, and clinical significance. J Nutr. 2004;134 (Suppl 10):2741S–897S.
4. Harris RA, Cynober L, Bier DM, Holloszy JO, Morris SM Jr, Shimomura Y, editors. Branched-chain amino acids: metabolism, physiological function, and application. J Nutr. 2005;36 (Suppl 1):207S–336S.
5. Dougherty DA. Cation- interactions involving aromatic amino acids. J Nutr. 2007;137 (6 Suppl 1):1504S–08S.
6. Wang Y, Tajkhorshid E. Molecular mechanisms of conduction and selectivity in aquaporin water channels. J Nutr. 2007;137(6 Suppl 1):1509S–15S.
7. Nagar B. c-Abl Tyrosine kinase and inhibition by the cancer drug Imatinib (Gleevec/STI-571). J Nutr. 2007;137(6 Suppl 1):1518S–23S.
8. Conigrave AD, Mun H-C, Lok H-C. Aromatic L-amino acids activate the calcium-sensing receptor. J Nutr. 2007;137(6 Suppl 1):1524S–27S.
9. Goddard WA III, Abrol R. 3-Dimensional structures of G protein-coupled receptors and binding sites of agonists and antagonists. J Nutr. 2007;137(6 Suppl 1):1528S–38S.
10. Fernstrom JD, Fernstrom MH. Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. J Nutr. 2007;137(6 Suppl 1):1539S–47S.
11. Matthews DE. An overview of phenylalanine and tyrosine kinetics in humans. J Nutr. 2007;137(6 Suppl 1):1549S–55S.
12. Nakamura K, Tanaka Y, Mitsubuchi H, Endo F. Animal models of tyrosinemia. J Nutr. 2007;137(6 Suppl 1):1556S–60S.
13. de Baulny HO, Abadie V, Feillet F, de Parscau L. Management of phenylketonuria and hyperphenylalaninemia. J Nutr. 2007;137(6 Suppl 1):1561S–63S.
14. Michals-Matalon K, Matalon R, Bhatia G, Koch R, Tyring SK, Guttler F. Response of phenylketonuria to tetrahydrobiopterin. J Nutr. 2007;137(6 Suppl 1):1564S–67S.
15. Hyland K. Inherited disorders affecting dopamine and serotonin: critical neurotransmitters derived from aromatic amino acids. J Nutr. 2007;137(6 Suppl 1):1568S–72S.
16. Pencharz PB, Hsu JW-C, Ball RO. Aromatic amino acid requirements in healthy human subjects. J Nutr. 2007;137(6 Suppl 1):1576S–78S.
17. Dejong CHC, van de Poll MCG, Soeters PB, Jalan R, Olde Damink SWM. Aromatic amino acid metabolism during liver failure. J Nutr. 2007;137(6 Suppl 1):1579S–85S.
18. Kopple JD. Phenylalanine and tyrosine metabolism in chronic kidney failure. J Nutr. 2007;137(6 Suppl 1):1586S–90S.
19. Fu Y-M, Meadows GG. Specific amino acid dependency regulates the cellular behavior of melanoma. J Nutr. 2007;137(6 Suppl 1):1591S–96S.
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