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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kaufman, S. Gu, P. Wang, G. A. |
| Description | Author Affiliation: Wang GA ( Laboratory of Neurochemistry, National Institute of Mental Health, Building 36, Room 3D30, Bethesda, MD 20892, USA. gawang@mit.edu); |
| Abstract | The regulatory domain of phenylalanine hydroxylase (PAH, EC ) consists of more than 100 amino acids at the N terminus, the removal of which significantly activates the enzyme. To study the regulatory properties controlled by the N terminus, a series of truncations and site-specific mutations were made in this region of rat PAH. These enzymes were expressed highly in Escherichia coli and purified through a pterin-conjugated Sepharose affinity column. The removal of the first 26 amino acids of the N terminus increased the activity by about 20-fold, but removal of the first 15 amino acids increased the activity by only 2-fold. Replacing serine-29 of rat PAH with cysteine from the same site of human PAH increased the activity by more than 4-fold. Mutation of serine to other amino acids with varying side chains: alanine, methionine, leucine, aspartic acid, asparagine, and arginine also resulted in significant activation, indicating a serine-specific inhibitory effect. But these site-specific mutants showed 30--40% lower activity when assayed with 6-methyl-5,6,7,8-tetrahydropterin. Stimulation of hydroxylase activity by preincubation of the enzyme with phenylalanine was inversely proportional to the activation state of all these mutants. Combined with recent crystal structures of PAH [Kobe, B. et al. (1999) Nat. Struct. Biol. 6, 442-448; and Erlandsen, H., Bjorgo, E., Flatmark, T. & Stevens, R. C. (2000) Biochemistry 39, 2208-2217], these data suggest that residues 16-26 have a controlling regulatory effect on the activity by interaction with the dihydroxypropyl side chain of (6R)-5,6,7,8-tetrahydrobiopterin. The serine/cysteine switch explains the difference in regulatory properties between human and rat PAH. The N terminus as a whole is important for maintaining rat PAH in an optimum catalytic conformation. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 4 |
| Volume Number | 98 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2001-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Phenylalanine Hydroxylase Physiology Amino Acid Sequence Amino Acid Substitution Animals Binding Sites Cysteine Genetics Metabolism Gene Expression Kinetics Molecular Sequence Data Mutagenesis, Site-Directed Phenylalanine Isolation & Purification Serine Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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