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28  structures 1444  species 2  interactions 1680  sequences 15  architectures

Family: HMG_CoA_synt_N (PF01154)

Summary: Hydroxymethylglutaryl-coenzyme A synthase N terminal

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This is the Wikipedia entry entitled "HMG-CoA synthase". More...

HMG-CoA synthase Edit Wikipedia article

3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (soluble)
Identifiers
Symbol HMGCS1
Alt. symbols HMGCS
Entrez 3157
HUGO 5007
OMIM 142940
RefSeq NM_002130
UniProt Q01581
Other data
Locus Chr. 5 p14-p13
3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (mitochondrial)
Identifiers
Symbol HMGCS2
Entrez 3158
HUGO 5008
OMIM 600234
RefSeq NM_005518
UniProt P54868
Other data
Locus Chr. 1 p13-p12
Hydroxymethylglutaryl-coenzyme A synthase N terminal
PDB 1txt EBI.jpg
staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
Identifiers
Symbol HMG_CoA_synt_N
Pfam PF01154
Pfam clan CL0046
InterPro IPR013528
PROSITE PDOC00942
Hydroxymethylglutaryl-coenzyme A synthase C terminal
PDB 1txt EBI.jpg
staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
Identifiers
Symbol HMG_CoA_synt_C
Pfam PF08540
Pfam clan CL0046
InterPro IPR013746
PROSITE PDOC00942

In molecular biology, HMG-CoA synthase EC 2.3.3.10 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 reaction

Mechanism[edit]

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.[1]

Species distribution[edit]

HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria.[2]

Eukaryotes[edit]

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.[3]

Cytosolic[edit]

The cytosolic form is the starting point of the mevalonate pathway, which leads to cholesterol and other sterolic and isoprenoid compounds).

Mitochondrial[edit]

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.[4] 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.

Bacteria[edit]

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.[5][6]

External links[edit]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ Goldstein J.L., Brown M.S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430
  5. ^ 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. 
  6. ^ 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. 

This article incorporates text from the public domain Pfam and InterPro IPR013746 This article incorporates text from the public domain Pfam and InterPro IPR013528

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Hydroxymethylglutaryl-coenzyme A synthase N terminal Provide feedback

No Pfam abstract.

Literature references

  1. 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 IPR013528

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 N-terminal domain of HMG-CoA synthase enzymes from both eukaryotes and prokaryotes.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan Thiolase (CL0046), which has the following description:

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 [1]. 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

Alignments

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RP75
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(4)
Full
(1680)
Representative proteomes NCBI
(1426)
Meta
(215)
RP15
(147)
RP35
(269)
RP55
(383)
RP75
(478)
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  Seed
(4)
Full
(1680)
Representative proteomes NCBI
(1426)
Meta
(215)
RP15
(147)
RP35
(269)
RP55
(383)
RP75
(478)
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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: HMG_CoA_synt;
Type: Family
Author: Finn RD, Bateman A
Number in seed: 4
Number in full: 1680
Average length of the domain: 165.20 aa
Average identity of full alignment: 41 %
Average coverage of the sequence by the domain: 40.45 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.5 20.5
Trusted cut-off 20.5 20.5
Noise cut-off 20.4 20.4
Model length: 174
Family (HMM) version: 12
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Species distribution

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Interactions

There are 2 interactions for this family. More...

HMG_CoA_synt_N HMG_CoA_synt_C

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HMG_CoA_synt_N domain has been found. There are 28 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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