Summary: Hydroxymethylglutaryl-coenzyme A synthase C terminal
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HMG-CoA synthase Edit Wikipedia article
|3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (soluble)|
|Locus||Chr. 5 p14-p13|
|3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (mitochondrial)|
|Locus||Chr. 1 p13-p12|
|Hydroxymethylglutaryl-coenzyme A synthase N terminal|
staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
|Hydroxymethylglutaryl-coenzyme A synthase C terminal|
staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
In molecular biology, HMG-CoA synthase EC 18.104.22.168 is an enzyme which catalyzes the reaction in which Acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). It is the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is over-activated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle, notably oxaloacetate. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis.
HMG-CoA synthase contains an important catalytic cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA.
In vertebrates, there are two different isozymes of the enzyme (cytosolic and mitochondrial); in humans the cytosolic form has only 60.6% amino acid identity with the mitochondrial form of the enzyme. HMG-CoA is also found in other eukaryotes such as insects, plants and fungi.
The cytosolic form is the starting point of the mevalonate pathway, which leads to cholesterol and other sterolic and isoprenoid compounds).
The mitochondrial form is responsible for the biosynthesis of ketone bodies. The gene for the mitochondrial form of the enzyme has three sterol regulatory elements in the 5' flanking region. These elements are responsible for decreased transcription of the message responsible for enzyme synthesis when dietary cholesterol is high in animals: the same is observed for 3-hydroxy-3-methylglutaryl-CoA and the low density lipoprotein receptor.
In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes.
- Theisen MJ, Misra I, Saadat D, Campobasso N, Miziorko HM, Harrison DH (November 2004). "3-hydroxy-3-methylglutaryl-CoA synthase intermediate complex observed in "real-time"". Proc. Natl. Acad. Sci. U.S.A. 101 (47): 16442–7. doi:10.1073/pnas.0405809101. PMC 534525. PMID 15498869.
- Bahnson BJ (November 2004). "An atomic-resolution mechanism of 3-hydroxy-3-methylglutaryl-CoA synthase". Proc. Natl. Acad. Sci. U.S.A. 101 (47): 16399–400. doi:10.1073/pnas.0407418101. PMC 534547. PMID 15546978.
- Bearfield JC, Keeling CI, Young S, Blomquist GJ, Tittiger C (April 2006). "Isolation, endocrine regulation and mRNA distribution of the 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMG-S) gene from the pine engraver, Ips pini (Coleoptera: Scolytidae)". Insect Mol. Biol. 15 (2): 187–95. doi:10.1111/j.1365-2583.2006.00627.x. PMID 16640729.
- Goldstein J.L., Brown M.S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430
- Steussy CN, Robison AD, Tetrick AM, Knight JT, Rodwell VW, Stauffacher CV, Sutherlin AL (December 2006). "A structural limitation on enzyme activity: the case of HMG-CoA synthase". Biochemistry 45 (48): 14407–14. doi:10.1021/bi061505q. PMID 17128980.
- Steussy CN, Vartia AA, Burgner JW, Sutherlin A, Rodwell VW, Stauffacher CV (November 2005). "X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA". Biochemistry 44 (43): 14256–67. doi:10.1021/bi051487x. PMID 16245942.
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Hydroxymethylglutaryl-coenzyme A synthase C terminal Provide feedback
No Pfam abstract.
Miziorko HM, Behnke CE; , J Biol Chem 1985;260:13513-13516.: Amino acid sequence of an active site peptide of avian liver mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. PUBMED:2865259 EPMC:2865259
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR013746
Synonym(s): 3-hydroxy-3-methylglutaryl-coenzyme A synthase, HMG-CoA synthase.
Hydroxymethylglutaryl-CoA synthase (EC) catalyses the condensation of acetyl-CoA with acetoacetyl-CoA to produce HMG-CoA and CoA, the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA synthase contains an important catalytic cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA [PUBMED:15498869].
HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria [PUBMED:15546978]. In vertebrates, there are two isozymes located in different subcellular compartments: a cytosolic form that is the starting point of the mevalonate pathway (leads to cholesterol and other sterolic and isoprenoid compounds), and a mitochondrial form responsible for ketone body biosynthesis. HMG-CoA is also found in other eukaryotes such as insects, plants and fungi [PUBMED:16640729]. In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes [PUBMED:17128980, PUBMED:16245942].
This entry represents the C-terminal domain of HMG-CoA synthase enzymes from both eukaryotes and prokaryotes.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||hydroxymethylglutaryl-CoA synthase activity (GO:0004421)|
|Biological process||isoprenoid biosynthetic process (GO:0008299)|
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Thiolases are ubiquitous and form a large superfamily. Thiolases can function either degradatively, in the beta-oxidation pathway of fatty acids, or biosynthetically. Biosynthetic thiolases catalyse the formation of acetoacetyl-CoA from two molecules of acetyl-CoA . This is one of the fundamental categories of carbon skeletal assembly patterns in biological systems and is the first step in a wide range of biosynthetic pathways . Thiolase are usually dimeric or tetrameric enzymes. Within each monomer there are two similar domains related by pseudo dyad. The N-terminal of these two domains contains a large insertion of about 100 amino acids.
The clan contains the following 13 members:ACP_syn_III ACP_syn_III_C Chal_sti_synt_C Chal_sti_synt_N FAE1_CUT1_RppA HMG_CoA_synt_C HMG_CoA_synt_N ketoacyl-synt Ketoacyl-synt_2 Ketoacyl-synt_C SpoVAD Thiolase_C Thiolase_N
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Curation and family details
|Author:||Finn RD, Bateman A|
|Number in seed:||10|
|Number in full:||2505|
|Average length of the domain:||142.60 aa|
|Average identity of full alignment:||23 %|
|Average coverage of the sequence by the domain:||53.54 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||5|
|Download:||download the raw HMM for this family|
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