1wl5
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Human cytosolic acetoacetyl-CoA thiolase
OverviewOverview
Thiolases belong to a superfamily of condensing enzymes that includes also, beta-ketoacyl acyl carrier protein synthases (KAS enzymes), involved in, fatty acid synthesis. Here, we describe the high resolution structure of, human cytosolic acetoacetyl-CoA thiolase (CT), both unliganded (at 2.3, angstroms resolution) and in complex with CoA (at 1.6 angstroms, resolution). CT catalyses the condensation of two molecules of acetyl-CoA, to acetoacetyl-CoA, which is the first reaction of the metabolic pathway, leading to the synthesis of cholesterol. CT is a homotetramer of exact 222, symmetry. There is an excess of positively charged residues at the, interdimer surface leading towards the CoA-binding pocket, possibly, important for the efficient capture of substrates. The geometry of the, catalytic site, including the three catalytic residues Cys92, His 353, Cys383, and the two oxyanion holes, is highly conserved between the human, and bacterial Zoogloea ramigera thiolase. In human CT, the first oxyanion, hole is formed by Wat38 (stabilised by Asn321) and NE2(His353), and the, second by N(Cys92) and N(Gly385). The active site of this superfamily is, constructed on top of four active site loops, near Cys92, Asn321, His353, and Cys383, respectively. These loops were used for the superpositioning, of CT on the bacterial thiolase and on the Escherichia coli KAS I. This, comparison indicates that the two thiolase oxyanion holes also exist in, KAS I at topologically equivalent positions. Interestingly, the hydrogen, bonding interactions at the first oxyanion hole are different in thiolase, and KAS I. In KAS I, the hydrogen bonding partners are two histidine NE2, atoms, instead of a water and a NE2 side-chain atom in thiolase. The, second oxyanion hole is in both structures shaped by corresponding main, chain peptide NH-groups. The possible importance of bound water molecules, at the catalytic site of thiolase for the reaction mechanism is discussed.
DiseaseDisease
Known disease associated with this structure: ACAT2 deficiency (1) OMIM:[100678]
About this StructureAbout this Structure
1WL5 is a Single protein structure of sequence from Homo sapiens with SO4 and GOL as ligands. Active as Acetyl-CoA C-acetyltransferase, with EC number 2.3.1.9 Full crystallographic information is available from OCA.
ReferenceReference
High resolution crystal structures of human cytosolic thiolase (CT): a comparison of the active sites of human CT, bacterial thiolase, and bacterial KAS I., Kursula P, Sikkila H, Fukao T, Kondo N, Wierenga RK, J Mol Biol. 2005 Mar 18;347(1):189-201. Epub 2005 Jan 19. PMID:15733928
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