http://rdf.ncbi.nlm.nih.gov/pubchem/conserveddomain/PSSMID187582
Outgoing Links
| Predicate | Object |
|---|---|
| abstract | ketoreductase (KR) and fatty acid synthase (FAS), complex (x) SDRs. Ketoreductase, a module of the multidomain polyketide synthase (PKS), has 2 subdomains, each corresponding to a SDR family monomer. The C-terminal subdomain catalyzes the NADPH-dependent reduction of the beta-carbonyl of a polyketide to a hydroxyl group, a step in the biosynthesis of polyketides, such as erythromycin. The N-terminal subdomain, an interdomain linker, is a truncated Rossmann fold which acts to stabilizes the catalytic subdomain. Unlike typical SDRs, the isolated domain does not oligomerize but is composed of 2 subdomains, each resembling an SDR monomer. The active site resembles that of typical SDRs, except that the usual positions of the catalytic Asn and Tyr are swapped, so that the canonical YXXXK motif changes to YXXXN. Modular PKSs are multifunctional structures in which the makeup recapitulates that found in (and may have evolved from) FAS. In some instances, such as porcine FAS, an enoyl reductase (ER) module is inserted between the sub-domains. Fatty acid synthesis occurs via the stepwise elongation of a chain (which is attached to acyl carrier protein, ACP) with 2-carbon units. Eukaryotic systems consist of large, multifunctional synthases (type I) while bacterial, type II systems, use single function proteins. Fungal fatty acid synthase uses a dodecamer of 6 alpha and 6 beta subunits. In mammalian type FAS cycles, ketoacyl synthase forms acetoacetyl-ACP which is reduced by the NADP-dependent beta-KR, forming beta-hydroxyacyl-ACP, which is in turn dehydrated by dehydratase to a beta-enoyl intermediate, which is reduced by NADP-dependent beta-ER. Polyketide synthesis also proceeds via the addition of 2-carbon units as in fatty acid synthesis. The complex SDR NADP-binding motif, GGXGXXG, is often present, but is not strictly conserved in each instance of the module. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold (alpha/beta folding pattern with a central beta-sheet), an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Classical SDRs are typically about 250 residues long, while extended SDRs are approximately 350 residues. Sequence identity between different SDR enzymes are typically in the 15-30% range, but the enzymes share the Rossmann fold NAD-binding motif and characteristic NAD-binding and catalytic sequence patterns. These enzymes catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. Classical SDRs have an TGXXX[AG]XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human prostaglandin dehydrogenase (PGDH) numbering). In addition to the Tyr and Lys, there is often an upstream Ser (Ser-138, PGDH numbering) and/or an Asn (Asn-107, PGDH numbering) contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Extended SDRs have additional elements in the C-terminal region, and typically have a TGXXGXXG cofactor binding motif. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type KRs have a TGXXXGX(1-2)G NAD(P)-binding motif. Some atypical SDRs have lost catalytic activity and/or have an unusual NAD(P)-binding motif and missing or unusual active site residues. Reactions catalyzed within the SDR family include isomerization, decarboxylation, epimerization, C=N bond reduction, dehydratase activity, dehalogenation, Enoyl-CoA reduction, and carbonyl-alcohol oxidoreduction. |
| title | KR_FAS_SDR_x |
| isDiscussedBy | http://rdf.ncbi.nlm.nih.gov/pubchem/reference/16710219 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/2976218 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/16710222 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/362665 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/24138116 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/7924710 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/28801668 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/5170140 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/23868174 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/32847553 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/20634749 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/23928768 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/20634752 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/18701164 http://rdf.ncbi.nlm.nih.gov/pubchem/reference/1524449 |
| type | http://purl.obolibrary.org/obo/SO_0000417 |
Incoming Links
Total number of triples: 25.