Acta Crystallographica Section D

Biological Crystallography

Volume 70, Part 2 (February 2014)

research papers

Acta Cryst. (2014). D70, 231-241    [ doi:10.1107/S1399004713026230 ]

Structural insights into the catalytic mechanism of human squalene synthase

C.-I. Liu, W.-Y. Jeng, W.-J. Chang, M.-F. Shih, T.-P. Ko and A. H.-J. Wang

Abstract: Squalene synthase (SQS) is a divalent metal-ion-dependent enzyme that catalyzes the two-step reductive `head-to-head' condensation of two molecules of farnesyl pyrophosphate to form squalene using presqualene diphosphate (PSPP) as an intermediate. In this paper, the structures of human SQS and its mutants in complex with several substrate analogues and intermediates coordinated with Mg2+ or Mn2+ are presented, which stepwise delineate the biosynthetic pathway. Extensive study of the SQS active site has identified several critical residues that are involved in binding reduced nicotinamide dinucleotide phosphate (NADPH). Based on mutagenesis data and a locally closed (JK loop-in) structure observed in the hSQS-(F288L)-PSPP complex, an NADPH-binding model is proposed for SQS. The results identified four major steps (substrate binding, condensation, intermediate formation and translocation) of the ordered sequential mechanisms involved in the `1'-1' isoprenoid biosynthetic pathway. These new findings clarify previous hypotheses based on site-directed mutagenesis and biochemical analysis.

PDB references: 3wef, 3weg, 3weh, 3wei, 3wej and 3wek

Keywords: squalene synthase; cholesterol synthesis; nicotinamide adenine dinucleotide; farnesyl pyrophosphate; terpenoids.

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[ doi:10.1107/S1399004713026230/mh5106sup1.pdf ]
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