Gcvh

H Multiple mitochondrial dysfunctions syndrome. MLEU:

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis Mtb proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of pairs of Mtb and non-TB mycobacterial NTM enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.

Gcvh

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GAB: NFB: PPP:

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PCC substr. Jiyao W et al. Conserved Protein Domain Family gcvH. TIGR gcvH Download alignment glycine cleavage system H protein This model represents the glycine cleavage system H protein, which shuttles the methylamine group of glycine from the P protein to the T protein. The mature protein is about residues long and contains a lipoyl group covalently bound to a conserved Lys residue. The genome of Aquifex aeolicus contains one protein scoring above the trusted cutoff and clustering with other bacterial H proteins, and four more proteins clustering together and scoring below the trusted cutoff; it seems doubtful that all of these homologs are authentic H protein. The Chlamydial homolog of H protein is nearly as divergent as the Aquifex outgroup, is not accompanied by P and T proteins, is not included in the seed alignment, and consequently also scores below the trusted cutoff. Specific Protein. Related Protein. Related Structure.

Gcvh

Glycine cleavage complex H protein GcvH is one of the four components that form the glycine cleavage complex GCS , essential for the synthesis of C 1 one-carbon units for cell metabolism, by the oxidative cleavage of glycine. The activity of this complex is induced in the presence of exogenous glycine, and is repressed by purines. GCS, in cooperation with GCA serine hydroxymethyltransferase regulates the endogenous levels of glycine and C 1 units in the cell. GcvH, the lipoamide containing component of the complex, plays an indispensable role in this reaction, as its prosthetic group shuttles between the active site of the three other components of the GCS complex sequentially. In environments rich in exogenous lipoic acid, GcvH is converted to lipoyl-GcvH by Lipoate protein ligase LplA , by the salvage pathway. When exogenous lipoic acid is deficient, it is post-translationally modified to lipoyl-GcvH by the consecutive action of two enzymes, a Lipoate protein ligase B LipB and b Lipoyl synthase LipA. Although, the crystal structure has been determined for Escherichia coli GcvH, no information exists for its interaction with LipB or LipA.

Lustery

FOC: DVT: PUC: BPYO: To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of pairs of Mtb and non-TB mycobacterial NTM enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. AEC: VPS: SFM: gcsh. PCHN: EGU: RZE:

Lipoic acid is synthesized by a remarkably atypical pathway in which the cofactor is assembled on its cognate proteins. An octanoyl moiety diverted from fatty acid synthesis is covalently attached to the acceptor protein, and sulfur insertion at carbons 6 and 8 of the octanoyl moiety form the lipoyl cofactor.

PLEP: gcshb BDR: SSPL: MAMB: gcsha gcshb. PTRU: SBIA: gcshb PMEI: gcsh LJA: Lj4g3v FVE: AGB: MCAL: Gcsh. PMUM: PGW: