Lanosterol biosynthesis pathway | Enzymes | IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY

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Lanosterol biosynthesis pathway

Lanosterol biosynthesis pathway C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Lanosterol is a precursor for cholesterol, which is synthesized primarily in the liver in a pathway often described as the mevalonate or HMG-CoA reductase pathway. The first two steps (formation of acetoacetyl CoA and the mitochondrial generation of (S)-3-hydroxy-3-methylglutaryl-CoA) are also associated with oxidation of fatty acids.

Enzymes

Targets of relevance to immunopharmacology are highlighted in blue

acetyl-CoA acetyltransferase 1 C Show summary »« Hide summary More detailed page

acetyl-CoA acetyltransferase 2 C Show summary »« Hide summary More detailed page

hydroxymethylglutaryl-CoA synthase 1 C Show summary »« Hide summary More detailed page

Target Id

638

Nomenclature

hydroxymethylglutaryl-CoA synthase 1

Previous and unofficial names

Genes

HMGCS1 (Hs), Hmgcs1 (Mm), Hmgcs1 (Rn)

Ensembl ID

ENSG00000112972 (Hs), ENSMUSG00000093930 (Mm), ENSRNOG00000016552 (Rn)

UniProtKB AC

Q01581 (Hs), Q8JZK9 (Mm), P17425 (Rn)

EC number

2.3.3.10

Acetyl CoA + H₂O + acetoacetyl CoA -> (S)-3-hydroxy-3-methylglutaryl-CoA + coenzyme A

Comment

HMGCoA synthase is found in cytosolic (HMGCoA synthase 1) and mitochondrial (HMGCoA synthase 2) versions; the former associated with (R)-mevalonate synthesis and the latter with ketogenesis.

hydroxymethylglutaryl-CoA synthase 2 C Show summary »« Hide summary More detailed page

hydroxymethylglutaryl-CoA reductase C Show summary »« Hide summary More detailed page

Target Id

639

Nomenclature

hydroxymethylglutaryl-CoA reductase

Previous and unofficial names

Genes

HMGCR (Hs), Hmgcr (Mm), Hmgcr (Rn)

Ensembl ID

ENSG00000113161 (Hs), ENSMUSG00000021670 (Mm), ENSRNOG00000016122 (Rn)

UniProtKB AC

P04035 (Hs), Q01237 (Mm), P51639 (Rn)

EC number

1.1.1.34	(S)-3-hydroxy-3-methylglutaryl-CoA + NADPH -> (R)-mevalonate + coenzyme A + NADP⁺
Reaction mechanism: First step: (S)-3-hydroxy-3-methylglutaryl-CoA + NADPH -> mevaldyl-CoA + NADP⁺ Second step: mevaldyl-CoA + H2O -> (R)-mevalonate + NADP⁺ [6]

Inhibitors

lovastatin (Competitive) pK_i 9.2 [1]

cerivastatin (Competitive) pK_i 8.2 [4]

rosuvastatin (Competitive) pIC₅₀ 8.3 [7]

atorvastatin (Competitive) pIC₅₀ 8.1 [7]

cerivastatin (Competitive) pIC₅₀ 8.0 [9]

simvastatin (Competitive) pIC₅₀ 8.0 [7]

fluvastatin (Competitive) pIC₅₀ 7.6 [7]

Comment

HMGCoA reductase is associated with intracellular membranes; enzymatic activity is inhibited by phosphorylation by AMP-activated kinase. The enzymatic reaction is a three-step reaction involving the intermediate generation of mevaldehyde-CoA and mevaldehyde.

mevalonate kinase C Show summary »« Hide summary More detailed page

phosphomevalonate kinase C Show summary »« Hide summary More detailed page

diphosphomevalonate decarboxylase C Show summary »« Hide summary More detailed page

Target Id

642

Nomenclature

diphosphomevalonate decarboxylase

Previous and unofficial names

Genes

MVD (Hs), Mvd (Mm), Mvd (Rn)

Ensembl ID

ENSG00000167508 (Hs), ENSMUSG00000006517 (Mm), ENSRNOG00000013376 (Rn)

UniProtKB AC

P53602 (Hs), Q99JF5 (Mm), Q62967 (Rn)

EC number

4.1.1.33

ATP + (R)-5-diphosphomevalonate -> ADP + isopentenyl diphosphate + CO₂ + PO₃^4-

isopentenyl-diphosphate Δ-isomerase 1 C Show summary »« Hide summary More detailed page

isopentenyl-diphosphate Δ-isomerase 2 C Show summary »« Hide summary More detailed page

geranylgeranyl diphosphate synthase C Show summary »« Hide summary More detailed page

farnesyl diphosphate synthase C Show summary »« Hide summary More detailed page

squalene synthase C Show summary »« Hide summary More detailed page

squalene monooxygenase C Show summary »« Hide summary More detailed page

lanosterol synthase C Show summary »« Hide summary More detailed page

References

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1. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E et al.. (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natl. Acad. Sci. U.S.A., 77 (7): 3957-61. [PMID:6933445]

2. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G. (2000) Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch. Biochem. Biophys., 373 (1): 231-41. [PMID:10620343]

3. Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD. (1993) Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc. Natl. Acad. Sci. U.S.A., 90 (1): 80-4. [PMID:8419946]

4. Carbonell T, Freire E. (2005) Binding thermodynamics of statins to HMG-CoA reductase. Biochemistry, 44 (35): 11741-8. [PMID:16128575]

5. Dunford JE, Kwaasi AA, Rogers MJ, Barnett BL, Ebetino FH, Russell RG, Oppermann U, Kavanagh KL. (2008) Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase. J. Med. Chem., 51 (7): 2187-95. [PMID:18327899]

6. Holdgate GA, Ward WH, McTaggart F. (2003) Molecular mechanism for inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by rosuvastatin. Biochem. Soc. Trans., 31 (Pt 3): 528-31. [PMID:12773150]

7. Istvan ES, Deisenhofer J. (2001) Structural mechanism for statin inhibition of HMG-CoA reductase. Science, 292 (5519): 1160-4. [PMID:11349148]

8. Seiki S, Frishman WH. (2009) Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia. Cardiol Rev, 17 (2): 70-6. [PMID:19367148]

9. Thilagavathi R, Kumar R, Aparna V, Sobhia ME, Gopalakrishnan B, Chakraborti AK. (2005) Three-dimensional quantitative structure (3-D QSAR) activity relationship studies on imidazolyl and N-pyrrolyl heptenoates as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitors by comparative molecular similarity indices analysis (CoMSIA). Bioorg. Med. Chem. Lett., 15 (4): 1027-32. [PMID:15686906]

10. Thompson JF, Danley DE, Mazzalupo S, Milos PM, Lira ME, Harwood HJ. (1998) Truncation of human squalene synthase yields active, crystallizable protein. Arch. Biochem. Biophys., 350 (2): 283-90. [PMID:9473303]

NC-IUPHAR subcommittee and family contributors

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Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Enzymes. Br J Pharmacol. 176 Issue S1: S297-S396.