Squalene synthase

Function

Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP) moieties to form squalene. Proceeds in two distinct steps. In the first half-reaction, two molecules of FPP react to form the stable presqualene diphosphate intermediate (PSQPP), with concomitant release of a proton and a molecule of inorganic diphosphate. In the second half-reaction, PSQPP undergoes heterolysis, isomerization, and reduction with NADPH or NADH to form squalene. It is the first committed enzyme of the sterol biosynthesis pathway.

Classification

Family (Pfam)

PF00494 SQS_PSY

InterPro

Isoprenoid_synthase_dom_sf, Squ/phyt_synthse, Squal_synth-like, Squalene/phytoene_synthase_CS, Trans_IPPS_euk-type, Trans_IPPS_HH

Functional cluster

Central Metabolic Enzymes (KARI/Glycolysis)

Experimental structures · PDB · 32

• 1EZF X-ray 2.15A
• 3ASX X-ray 2.00A
• 3LEE X-ray 3.20A
• 3Q2Z X-ray 2.00A
• 3Q30 X-ray 2.00A
• 3V66 X-ray 1.80A
• 3VJ8 X-ray 1.52A
• 3VJ9 X-ray 1.52A
• 3VJA X-ray 1.76A
• 3VJB X-ray 2.05A
• 3VJC X-ray 1.89A
• 3WC9 X-ray 2.82A
• … and 20 more

A predicted model is available from AlphaFold.

Gene Ontology · 12

• GO:0098554 cytoplasmic side of endoplasmic reticulum membrane
• GO:0005783 endoplasmic reticulum
• GO:0005789 endoplasmic reticulum membrane
• GO:0016020 membrane
• GO:0046872 metal ion binding
• GO:0051996 squalene synthase [NAD(P)H] activity
• GO:0006695 cholesterol biosynthetic process
• GO:0033489 cholesterol biosynthetic process via desmosterol
• GO:0033490 cholesterol biosynthetic process via lathosterol
• GO:0045338 farnesyl diphosphate metabolic process
• GO:0006694 steroid biosynthetic process
• GO:0036197 zymosterol biosynthetic process

Disease associations

• squalene synthase deficiency MONDO:0032566

Drugs targeting this protein · 1

• LAPAQUISTAT ACETATE inhibitor

Related proteins · sequence + function similarity

• Squalene synthase 1.00
• Squalene synthase 0.99
• Squalene synthase 0.99
• Squalene synthase 0.98
• Squalene synthase 8 0.93
• Squalene synthase 0.92
• Squalene synthase 1 0.92
• Squalene synthase 1 0.92
• Squalene synthase 0.92
• Squalene synthase 0.91
• Squalene synthase 10 0.91
• Squalene synthase 12 0.91

Co-cited proteins · studied together in the literature

• C-8 sterol isomerase erg2 1 shared papers
• Squalene synthase 1 shared papers
• Ergosterol biosynthetic protein 28 1 shared papers
• C-22 sterol desaturase ERG5 1 shared papers

Literature · 14 cited papers

• Squalene synthase deficiency: clinical, biochemical, and molecular characterization of a defect in cholesterol biosynthesis. Am. J. Hum. Genet. · 2018
• N-terminome analysis of the human mitochondrial proteome. Proteomics · 2015
• Structural insights into the catalytic mechanism of human squalene synthase. Acta Crystallogr. D · 2014
• An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• K45R variant of squalene synthase increases total cholesterol levels in two study samples from a French Canadian population. Hum. Mutat. · 2008
• DNA sequence and analysis of human chromosome 8. Nature · 2006
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat. Genet. · 2004
• Crystal structure of human squalene synthase. A key enzyme in cholesterol biosynthesis. J. Biol. Chem. · 2000
• Conservation between human and fungal squalene synthetases: similarities in structure, function, and regulation. Mol. Cell. Biol. · 1993
• Cloning, expression and characterisation of the cDNA encoding human hepatic squalene synthase, and its relationship to phytoene synthase. Gene · 1993
• … and 2 more in the literature graph