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Supplement: Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application: SESSION 2

Biology and Biochemistry: Discussion of Session 2^1,2

³ Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya, 466-8555 Japan and ⁴ Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

^* To whom correspondence should be addressed. E-mail: shimomura.yoshiharu{at}nitech.ac.jp.

In this session, there were 4 talks focusing on: 1) the structure and regulation of c-Abl tyrosine kinase (1); 2) the activation of the calcium-sensing receptor by aromatic amino acids (2); 3) the computational methods for predicting three-dimensional (3D) structures and ligand-binding sites of G protein-coupled receptors (GPCR) (3); and 4) the roles of tyrosine and phenylalanine in catecholamine synthesis and function in the brain (4).

The discussion session was opened by Dr. Shimomura with summaries of the 4 talks, followed by discussion that focused primarily on the presentations of Dr. Goddard and Dr. Fernstrom. Dr. William A. Goddard III dealt with the problem of developing drugs targeted to GPCR, a large family of transmembrane receptors that play critical roles in cell communication and in mediating senses such as smell, taste, vision, and pain. The application of the usual structure-based design methodologies to develop drugs with improved specificity for particular GPCR is not feasible because, with the exception of bovine rhodopsin, there are no experimental 3D structures available for these receptors, because of the great difficulty in determining the structures of transmembrane proteins. Therefore, Dr. Goddard used the MembStruk computational method to predict 3D structures of over 30 GPCR, followed by the HierDock computational method to predict the ligand-binding site and relative binding energies for a variety of agonists and antagonists, focusing on GPCR for biogenic amines. The predicted 3D structures and calculated relative ligand-binding energies showed good qualitative agreement with experimental determinations of ligand-binding affinities. These findings indicate that the computational methods represent a feasible approach for the rational design of new drugs in cases where 3D structures of the drug targets are not known. In the discussion period, Dr. Goddard commented on some limitations of the methodology, particularly with regard to systems where ligands bind with weak affinity, but noted that efforts for refining the computational methods are ongoing.

During the discussion of Dr. Fernstrom's talk, it was commented that, in contrast to pools in brain tissue, short-term changes in pool sizes of amino acids and their metabolites in the cerebrospinal fluid were difficult to interpret in relation to metabolism in brain. It was noted that long-term dietary supplementation might result in adaptive changes in levels of some of the enzymes involved in the metabolism of the aromatic amino acids in the brain; however, earlier studies indicated that tyrosine hydroxylase activity did not change under these conditions, but this does not rule out the possibility that levels of some of the other enzymes might undergo adaptive changes. Regarding the possibility that the pathways studied by Dr. Fernstrom might play a role in the central nervous system side effects in phenylketonuria, the comment was made that relatively little is known about that possibility and that active investigation in that area largely ceased quite some time ago. There also was some discussion of the extent to which proteins with different amino acid compositions might differentially affect catecholamine synthesis.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented at the "Conference on Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application" held July 20–21, 2006 in Vancouver, Canada. The conference was sponsored by Ajinomoto Company, Inc. The organizing committee for the symposium and Guest Editors for the supplement were Katsuji Takai, Dennis M. Bier, Luc Cynober, Sidney M. Morris, Jr., and Yoshiharu Shimomura. Guest Editor disclosure: Expenses to travel to the meeting were paid by Ajinomoto Company, Inc. for K. Takai, D. M. Bier, L. Cynober, S. M. Morris, Jr., and Y. Shimomura; D. M. Bier has consulted for Ajinomoto Company, Inc. on scientific issues.

² Author disclosures: Y. Shimomura, travel expenses paid by the Ajinomoto Company, Inc.; S. M. Morris, travel expenses paid by the Ajinomoto Company, Inc.

	LITERATURE CITED

TOP LITERATURE CITED

 

1. Nagar B. c-Abl tyrosine kinase and inhibition by the cancer drug Imatinib (Gleenvec/STI-571). J Nutr. 2007;137:1518S–23S.[Abstract/Free Full Text]

2. Conigrave AD, Mun H-C, Lok H-C. Aromatic L-amino acids activate the calcium-sensing receptor. J Nutr. 2007;137:1524S–27S.[Abstract/Free Full Text]

3. Goddard WA III. 3-D structure and binding sites of biogenic amines and other ligands to G-protein coupled receptors. J Nutr. 2007;137:1528S–38S.[Abstract/Free Full Text]

4. Fernstrom JD, Fernstrom MH. Tyrosine, phenylalanine, and cathecolamine sythesis and function in the brain. J Nutr. 2007;137:1539S–47S.[Abstract/Free Full Text]

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