hydroxymethylglutaryl-CoA synthase 1 | Lanosterol biosynthesis pathway | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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hydroxymethylglutaryl-CoA synthase 1

Target id: 638

Nomenclature: hydroxymethylglutaryl-CoA synthase 1

Family: Lanosterol biosynthesis pathway

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 520 5p14-p13 HMGCS1 3-hydroxy-3-methylglutaryl-CoA synthase 1
Mouse - 520 13 66.0 cM; 13 Hmgcs1 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1
Rat - 520 2q16 Hmgcs1 3-hydroxy-3-methylglutaryl-CoA synthase 1
Previous and Unofficial Names
acetoacetyl coenzyme A transacetase | HMG-CoA synthase | hydroxymethylglutaryl coenzyme A-condensing enzyme | HMGCS | hydroxymethylglutaryl-CoA synthase, cytoplasmic | cytosolic HMGCoA synthase
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human 3-hydroxy-3-methylglutaryl CoA synthase I
PDB Id:  2P8U
Resolution:  2.0Å
Species:  Human
References:  6
Enzyme Reaction
EC Number: 2.3.3.10 Acetyl CoA + H2O + acetoacetyl CoA -> (S)-3-hydroxy-3-methylglutaryl-CoA + coenzyme A
Substrates and Reaction Kinetics
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
acetyl CoA Hs Km 2.9x10-5 M pKm 4.5 pH 8.2, 30ºC 5
acetyl CoA Hs Km 7.3x10-5 M pKm 4.1 Recombinant human HMG CoA synthase was produced in Escherichia coli, microplate analysis for purified enzyme. In vitro. pH 8.2, 24ºC ΔA412 nm assay. DTNB measurement of CoASH formation. 130µM Acetyl-CoA, 7µM acetoacetyl-CoA. 1
acetyl CoA Hs Km 7.6x10-5 M pKm 4.1 Recombinant human HMG CoA synthase was produced in Escherichia coli, microplate analysis for purified enzyme. In vitro. pH 8.0, 30ºC Measured at wavelength 300 nm using a standard spectrophotometric assay. Concentration of acetoacetyl-CoA was 7µM, Acetyl-CoA ranged from 10 to 1000µM 1
acetyl CoA Hs Km 8.4x10-5 M pKm 4.1 Recombinant human HMG CoA synthase was produced in Escherichia coli, microplate analysis for purified enzyme. In vitro. pH 8.0, 30ºC ΔA412 nm assay (DTNB measurement of coenzyme A formation). Substrate concentrations were 130µM acetyl-CoA and 7µM acetoacetyl-CoA. 1
acetoacetyl CoA Hs Km 5x10-6 M pKm 5.3 Recombinant human HMG CoA synthase was produced in Escherichia coli, microplate analysis for purified enzyme. In vitro. pH 8.0, 30ºC ΔA412 nm assay (DTNB measurement of coenzyme A formation). Substrate concentrations were 130µM acetyl-CoA and 7µM acetoacetyl-CoA. 1
acetyl CoA Hs Vmax 0.67 µmol/min/mg Recombinant human HMG CoA synthase was produced in Escherichia coli, microplate analysis for purified enzyme. In vitro. Microgram quantities of enzyme used. pH 8.0, 24ºC ΔA412 nm assay. DTNB measurement of CoASH formation. 130µM Acetyl-CoA, 7µM acetoacetyl-CoA. 1
acetyl CoA Hs Vmax 1.04 µmol/min/mg Recombinant human HMG CoA synthase was produced in Escherichia coli, microplate analysis for purified enzyme. In vitro. Microgram quantities of enzyme used. pH 8.0, 30ºC ΔA412 nm assay (DTNB measurement of coenzyme A formation). Substrate concentrations were 130µM acetyl-CoA and 7µM acetoacetyl-CoA. 1
acetyl CoA Hs Vmax 1.06 µmol/min/mg Recombinant human HMG CoA synthase was produced in Escherichia coli, microplate analysis for purified enzyme.In vitro. Microgram quantities of enzyme used. pH 8.0, 30ºC Measured at wavelength 300 nm using a standard spectrophotometric assay. Concentration of acetoacetyl-CoA was 7µM, Acetyl-CoA ranged from 10 to 1000µM 1

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
(S)-3-hydroxy-3-methylglutaryl-CoA Hs Feedback inhibition 5.5 – 5.9 pKi 1
pKi 5.5 – 5.9 (Ki 3.1x10-6 – 1.1x10-6 M) [1]
Conditions: pH 8.0, 24°C. Concentration of reagents: 7µM acetoacetyl-CoA, 130µM acetyl-CoA
L-659,699 Rn Unknown 7.0 pIC50 3-4
pIC50 7.0 (IC50 1x10-7 M) [3-4]
View species-specific inhibitor tables
Inhibitor Comments
The determination of the crystal structure of human HMGSC in its two isoforms (HMGCS1- cytoplasmic form, and HMNGCS2-mitochondrial form) provides a structural basis for the development of inhibitors for this enzyme, some of which may be isoform specific [6]. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide modified amino acid residues also inhibits HMGS1 [2]. Polyheterocyclic compound 2-benzyl-9-(3,6-dioxocyclohexa-1,4-dienyl)-2,3,7,8-tetrahydrol-6H-pyrido[1,2-a]-pyrazine-1,4-dione had a Ki of below 10 micromolar for HMGCS1 [1].
General Comments
HMGCoA synthase is found in cytosolic (HMGCoA synthase 1) and mitochondrial (HMGCoA synthase 2) versions; the former associated with synthesis and the latter with ketogenesis.

References

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1. Andrew Skaff D, Miziorko HM. (2010) A visible wavelength spectrophotometric assay suitable for high-throughput screening of 3-hydroxy-3-methylglutaryl-CoA synthase. Anal. Biochem., 396 (1): 96-102. [PMID:19706283]

2. Chun KY, Vinarov DA, Miziorko HM. (2000) 3-Hydroxy-3-methylglutaryl-CoA synthase: participation of invariant acidic residues in formation of the acetyl-S-enzyme reaction intermediate. Biochemistry, 39 (47): 14670-81. [PMID:11087424]

3. Greenspan MD, Bull HG, Yudkovitz JB, Hanf DP, Alberts AW. (1993) Inhibition of 3-hydroxy-3-methylglutaryl-CoA synthase and cholesterol biosynthesis by beta-lactone inhibitors and binding of these inhibitors to the enzyme. Biochem. J., 289 ( Pt 3): 889-95. [PMID:8094614]

4. Greenspan MD, Yudkovitz JB, Lo CY, Chen JS, Alberts AW, Hunt VM, Chang MN, Yang SS, Thompson KL, Chiang YC et al.. (1987) Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699. Proc. Natl. Acad. Sci. U.S.A., 84 (21): 7488-92. [PMID:2890166]

5. Rokosz LL, Boulton DA, Butkiewicz EA, Sanyal G, Cueto MA, Lachance PA, Hermes JD. (1994) Human cytoplasmic 3-hydroxy-3-methylglutaryl coenzyme A synthase: expression, purification, and characterization of recombinant wild-type and Cys129 mutant enzymes. Arch. Biochem. Biophys., 312 (1): 1-13. [PMID:7913309]

6. Shafqat N, Turnbull A, Zschocke J, Oppermann U, Yue WW. (2010) Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. J. Mol. Biol., 398 (4): 497-506. [PMID:20346956]

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