Constructing tailored isoprenoid products by structure-guided modification of geranylgeranyl reductase

Structure. 2014 Jul 8;22(7):1028-36. doi: 10.1016/j.str.2014.05.007. Epub 2014 Jun 19.


The 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Archaeal Proteins / chemistry*
  • Archaeal Proteins / genetics
  • Archaeal Proteins / metabolism
  • Crystallography, X-Ray
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Oxidoreductases / chemistry*
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Polyisoprenyl Phosphates / chemistry
  • Polyisoprenyl Phosphates / metabolism
  • Protein Binding
  • Protein Structure, Tertiary*
  • Substrate Specificity
  • Sulfolobus acidocaldarius / enzymology
  • Sulfolobus acidocaldarius / genetics
  • Sulfolobus acidocaldarius / metabolism
  • Terpenes / chemistry*
  • Terpenes / metabolism


  • Archaeal Proteins
  • Polyisoprenyl Phosphates
  • Terpenes
  • Oxidoreductases
  • geranylgeranyl reductase
  • geranylgeranyl pyrophosphate