Document Detail

Substrate inhibition of D-amino acid transaminase and protection by salts and by reduced nicotinamide adenine dinucleotide: isolation and initial characterization of a pyridoxo intermediate related to inactivation.
MedLine Citation:
PMID:  9485439     Owner:  NLM     Status:  MEDLINE    
D-Amino acid transaminase, a pyridoxal phosphate (PLP) enzyme, is inactivated by its natural substrate, D-alanine, concomitant with its alpha-decarboxylation [Martinez del Pozo, A., Yoshimura, T., Bhatia, M. B., Futaki, S., Manning, J. M., Ringe, D., and Soda, K. (1992) Biochemistry 31, 6018-6023; Bhatia, M. B., Martinez del Pozo, A., Ringe, D., Yoshimura, T., Soda, K., and Manning, J. M. (1993) J. Biol. Chem. 268, 17687-17694]. beta-Decarboxylation of d-aspartate to d-alanine leads also to this inactivation [Jones, W. M., van Ophem, P. W., Pospischil, M. A., Ringe, D., Petsko, G., Soda, K., and Manning, J. M. (1996) Protein Sci. 5, 2545-2551]. Using a high-performance liquid chromatography-based method for the determination of pyridoxo cofactors, we detected a new intermediate closely related to the inactivation by d-alanine; its formation occurred at the same rate as the inactivation and upon reactivation it reverted to PLP. Conditions were found under which it was characterized by ultraviolet-visible spectral analysis and mass spectroscopy; it is a pyridoxamine phosphate-like compound with a C2 fragment derived from the substrate attached to the C'-4 of the pyridinium ring and it has a molecular mass of 306 consistent with this structure. In the presence of d-serine, slow accumulation of a quinonoid intermediate is also related to inactivation. The inactivation can be prevented by salts, which possibly stabilize the protonated aldimine coenzyme complex. The reduced cofactor, nicotinamide adenine dinucleotide, prevents D-aspartate-induced inactivation. Both of these events also are related to formation of the novel intermediate.
P W van Ophem; S D Erickson; A Martinez del Pozo; I Haller; B T Chait; T Yoshimura; K Soda; D Ringe; G Petsko; J M Manning
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Biochemistry     Volume:  37     ISSN:  0006-2960     ISO Abbreviation:  Biochemistry     Publication Date:  1998 Mar 
Date Detail:
Created Date:  1998-04-03     Completed Date:  1998-04-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2879-88     Citation Subset:  IM    
Northeastern University, Boston, Massachusetts 02115, USA.
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MeSH Terms
Alanine / pharmacology
Chromatography, High Pressure Liquid
D-Alanine Transaminase
Enzyme Inhibitors / pharmacology
NAD / metabolism*
Pyridoxal Phosphate / analogs & derivatives,  metabolism*
Pyridoxamine / analogs & derivatives,  metabolism
Pyruvic Acid / metabolism
Serine / pharmacology
Transaminases / antagonists & inhibitors*
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Salts; 127-17-3/Pyruvic Acid; 447-05-2/pyridoxine 5-phosphate; 529-96-4/pyridoxamine phosphate; 53-84-9/NAD; 54-47-7/Pyridoxal Phosphate; 56-41-7/Alanine; 56-45-1/Serine; 85-87-0/Pyridoxamine; EC 2.6.1.-/Transaminases; EC Transaminase

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