Human fatty acid synthase: Structure and substrate selectivity of the thioesterase domain
| Autor: | Salih J. Wakil, Subrahmanyam S. Chirala, Florante A. Quiocho, Zi-Wei Gu, Bornali Chakravarty |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Protein Folding Stereochemistry Molecular Sequence Data Crystallography X-Ray Substrate Specificity Palmitic acid chemistry.chemical_compound Thioesterase Catalytic Domain Hydrolase Catalytic triad Humans Amino Acid Sequence Peptide sequence chemistry.chemical_classification Multidisciplinary Sequence Homology Amino Acid biology Chemistry Fatty acid Biological Sciences Protein Structure Tertiary Fatty acid synthase Biochemistry biology.protein Beta-ketoacyl-ACP synthase Fatty Acid Synthases |
| Zdroj: | Proceedings of the National Academy of Sciences. 101:15567-15572 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0406901101 |
| Popis: | Human fatty acid synthase is a large homodimeric multifunctional enzyme that synthesizes palmitic acid. The unique carboxyl terminal thioesterase domain of fatty acid synthase hydrolyzes the growing fatty acid chain and plays a critical role in regulating the chain length of fatty acid released. Also, the up-regulation of human fatty acid synthase in a variety of cancer makes the thioesterase a candidate target for therapeutic treatment. The 2.6-Å resolution structure of human fatty acid synthase thioesterase domain reported here is comprised of two dissimilar subdomains, A and B. The smaller subdomain B is composed entirely of α-helices arranged in an atypical fold, whereas the A subdomain is a variation of the α/β hydrolase fold. The structure revealed the presence of a hydrophobic groove with a distal pocket at the interface of the two subdomains, which constitutes the candidate substrate binding site. The length and largely hydrophobic nature of the groove and pocket are consistent with the high selectivity of the thioesterase for palmitoyl acyl substrate. The structure also set the identity of the Asp residue of the catalytic triad of Ser, His, and Asp located in subdomain A at the proximal end of the groove. |
| Databáze: | OpenAIRE |
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