Amino acid hydroxylases

Pterin-dependent amino acid hydroxylases 96CRV2659. 

An intriguing puzzle in NOS catalysis is the precise role of H4B. The traditional function of H4B is in aromatic amino acid metabolism where H4B directly participates in the hydroxylation reaction via a nonheme iron. However, the NOS pterin site has no similarity to the pterin site in the hydroxylases, nor does NOS have a nonheme iron to assist pterin in substrate hydroxylation as in the amino acid hydroxylases 111). NOS more closely resembles pterin-containing enz5unes that have a redox function 81). In particular, N3 and the 03 amino group form H-bonds with either GIu or Asp residues in a series of pterin enzymes 112-116) similar to NOS, except that NOS utilizes the heme propionate (Fig. 6). 

AROMATIC AMINO ACID-GLYOXYLATE AMINOTRANSFERASE Aromatic amino acid hydroxylases, PHENYLALANINE HYDROXYLASE TYROSINE HYDROXYLASE TRYPTOPHAN HYDROXYLASE ARRHENIUS CONSTANT... 

The first step of 5-HT biosynthesis is catalyzed by the rate-hmiting enzyme tryptophan hydroxylase (TPH). Two isoforms, TPHl and TPH2, have been identified in the periphery and in 5-HT neurons, respectively. Both isoforms are members of the aromatic amino acid hydroxylase gene family, together with phenylalanine (PAH) and tyrosine hydroxylases (TH). The human TPHl gene located on chromosome llplS.l, spans a region of 30 kb, contains at... 

Benkovic and co-workers also isolated spirocyclic 2-amino-4(5/7)-oxazolones during their studies on pterin-dependent amino acid hydroxylases (Scheme 6.24). Reaction of 91 with 0-methyl hydroxylamine or semicarbazide at pH 4.8 yielded 92a and 92b, respectively. The authors showed that 92 does not simply result from reaction of the corresponding oxazolidinedione with either reagent. Further, by using H2 0 as the solvent they demonstrated that there was no incorporation into the product. Two different but precedented mechanisms were proposed to account for this rearrangement. The stereochemistry of 92b was confirmed by single-crystal X-ray. 

Studies with the macrophage NOS were the first to show that NO synthesis was partially dependent on added Hbiopterin (Kwon et ai, 1989 Stuehr et al., 1990), which is a redox active cofactor utilized by the aromatic amino acid hydroxylases (Nichol et al., 1985). The requirement for H4biopterin has since been expanded to include all NOS isoforms studied to date. Mayer et al. (1990)... 

THE AROMATIC AMINO ACID HYDROXYLASE MECHANISM A PERSPECTIVE FROM COMPUTATIONAL CHEMISTRY... 

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