Structural insights into the catalytic mechanism of human squalene synthase

Chia I. Liu, Wen-Yih Jeng, Wei Jung Chang, Min Fang Shih, Tzu Ping Ko, Andrew H.J. Wang

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)231-241
Number of pages11
JournalActa Crystallographica Section D: Biological Crystallography
Volume70
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1

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Farnesyl-Diphosphate Farnesyltransferase
Niacinamide
Biosynthetic Pathways
Phosphates
Squalene
Terpenes
Site-Directed Mutagenesis
Mutagenesis
Catalytic Domain
Metals
Ions
Enzymes

All Science Journal Classification (ASJC) codes

  • Structural Biology

Cite this

Liu, Chia I. ; Jeng, Wen-Yih ; Chang, Wei Jung ; Shih, Min Fang ; Ko, Tzu Ping ; Wang, Andrew H.J. / Structural insights into the catalytic mechanism of human squalene synthase. In: Acta Crystallographica Section D: Biological Crystallography. 2014 ; Vol. 70, No. 2. pp. 231-241.
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Structural insights into the catalytic mechanism of human squalene synthase. / Liu, Chia I.; Jeng, Wen-Yih; Chang, Wei Jung; Shih, Min Fang; Ko, Tzu Ping; Wang, Andrew H.J.

In: Acta Crystallographica Section D: Biological Crystallography, Vol. 70, No. 2, 01.02.2014, p. 231-241.

Research output: Contribution to journalArticle

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