4opc
Constructing tailored isoprenoid products by structure-guided modification of geranylgeranyl reductase.Constructing tailored isoprenoid products by structure-guided modification of geranylgeranyl reductase.
Structural highlights
FunctionGGR_SULAC Is involved in the reduction of 2,3-digeranylgeranylglycerophospholipids (unsaturated archaeols) into 2,3-diphytanylglycerophospholipids (saturated archaeols) in the biosynthesis of archaeal membrane lipids. Catalyzes the formation of archaetidic acid (2,3-di-O-phytanyl-sn-glyceryl phosphate) from 2,3-di-O-geranylgeranylglyceryl phosphate (DGGGP) via the hydrogenation of each double bond of the isoprenoid chains. Is not active with NADPH or NADH as an electron donor; the physiological reducing agent is unknown. Is also active on the more upstream precursors of membrane lipid biosynthesis, catalyzing the complete reduction of 3-O-geranylgeranylglyceryl phosphate (GGGP) to 3-O-phytanylglyceryl phosphate, and the partial reduction of geranylgeranyl diphosphate (GGPP) to phytyl diphosphate, thus reducing three of four GGPP double bonds and preserving the allylic double bond (at position 2). This reaction product is a reactive prenyl donor, which can be used as a substrate by archaeal prenyltransferases such as GGGP synthases.[1] [2] [3] Publication Abstract from PubMedThe archaeal enzyme geranylgeranyl reductase (GGR) catalyzes hydrogenation of carbon-carbon double bonds to produce the saturated alkyl chains of the organism's unusual isoprenoid-derived cell membrane. Enzymatic reduction of isoprenoid double bonds is of considerable interest both to natural products researchers and to synthetic biologists interested in the microbial production of isoprenoid drug or biofuel molecules. Here we present crystal structures of GGR from Sulfolobus acidocaldarius, including the structure of GGR bound to geranylgeranyl pyrophosphate (GGPP). The structures are presented alongside activity data that depict the sequential reduction of GGPP to H6GGPP via the intermediates H2GGPP and H4GGPP. We then modified the enzyme to generate sequence variants that display increased rates of H6GGPP production or are able to halt the extent of reduction at H2GGPP and H4GGPP. Crystal structures of these variants not only reveal the structural bases for their altered activities; they also shed light onto the catalytic mechanism employed. Constructing Tailored Isoprenoid Products by Structure-Guided Modification of Geranylgeranyl Reductase.,Kung Y, McAndrew RP, Xie X, Liu CC, Pereira JH, Adams PD, Keasling JD Structure. 2014 Jun 17. pii: S0969-2126(14)00148-8. doi:, 10.1016/j.str.2014.05.007. PMID:24954619[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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