6u1v | pdb_00006u1v

Crystal structure of acyl-ACP/acyl-CoA dehydrogenase from allylmalonyl-CoA and FK506 biosynthesis, TcsD

spinqualitylabelsall models 6u1v, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6u1v is a 4 chain structure with sequence from Streptomyces tsukubensis NRRL18488. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: FDA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function I2MTW3_STRT9 Publication Abstract from PubMed Terminal alkenes are easily derivatized, making them desirable functional group targets for polyketide synthase (PKS) engineering. However, they are rarely encountered in natural PKS systems. One mechanism for terminal alkene formation in PKSs is through the activity of an acyl-CoA dehydrogenase (ACAD). Herein, we use biochemical and structural analysis to understand the mechanism of terminal alkene formation catalyzed by an gamma,-ACAD from the biosynthesis of the polyketide natural product FK506, TcsD. While TcsD is homologous to canonical alpha,beta-ACADs, it acts regioselectively at the gamma,-position and only on alpha,beta-unsaturated substrates. Furthermore, this regioselectivity is controlled by a combination of bulky residues in the active site and a lateral shift in the positioning of the FAD cofactor within the enzyme. Substrate modeling suggests that TcsD utilizes a novel set of hydrogen bond donors for substrate activation and positioning, preventing dehydrogenation at the alpha,beta position of substrates. From the structural and biochemical characterization of TcsD, key residues that contribute to regioselectivity and are unique to the protein family were determined and used to identify other putative gamma,-ACADs that belong to diverse natural product biosynthetic gene clusters. These predictions are supported by the demonstration that a phylogenetically distant homolog of TcsD also regioselectively oxidizes alpha,beta-unsaturated substrates. This work exemplifies a powerful approach to understand unique enzymatic reactions and will facilitate future enzyme discovery, inform enzyme engineering, and aid natural product characterization efforts. Structural mechanism of regioselectivity in an unusual bacterial acyl-CoA dehydrogenase.,Blake-Hedges JM, Pereira JH, Cruz-Morales P, Thompson MG, Barajas JF, Chen J, Krishna RN, Chan LJG, Nimlos D, Alonso-Martinez C, Baidoo EEK, Chen Y, Gin JW, Katz L, Petzold CJ, Adams PD, Keasling JD J Am Chem Soc. 2019 Dec 3. doi: 10.1021/jacs.9b09187. PMID:31793780 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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