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MetaCyc Enzyme: peroxisomal multifunctional enzyme type 2

Gene: Hsd17b4 Accession Number: G-10923 (MetaCyc)

Synonyms: D-bifunctional protein, perMFE2, MFE2, MFE-2, DBP, D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein, perMFE-2, 17β-hydroxysteroid dehydrogenase type 4, 17β-HSD type 4

Species: Rattus norvegicus

Subunit composition of peroxisomal multifunctional enzyme type 2 = [Hsd17b4]2
         peroxisomal multifunctional enzyme type 2 subunit = Hsd17b4

Summary:
The native enzyme purified from rat liver was determined to be a homodimer of a 77 kDa polypeptide. A homodimeric 46 kDa proteolytic fragment of it contained the reversible hydratase/dehydratase activity [Jiang96].

This bifunctional enzyme catalyzes the second (hydratase) and third (dehydrogenase) steps in the peroxisomal β-oxidation of the side chain of bile acid biosynthetic intermediates (reviewed in [Russell03].

The crystal structure of a recombinant, homodimeric fragment of the polypeptide, which contains the dehydrogenase activity, was determined at 2.38Å resolution [Haapalainen03]. Expression and purification of this recombinant fragment in Escherichia coliand its activity using (24E)-3α,7α,12α-trihydroxy-5β-cholest-24-enoyl-CoA was demonstrated [Qin97].

Mutations in the human gene encoding this enzyme may result in liver failure and neurological deficiencies (reviewed in [Russell03]).

Locations: peroxisome

Map Position: [45,157,435 -> 45,251,528]

Molecular Weight of Polypeptide: 79.428 kD (from nucleotide sequence)

Unification Links: Entrez-gene:79244 , PhosphoSite:P97852 , Pride:P97852 , Protein Model Portal:P97852 , SMR:P97852 , String:10116.ENSRNOP00000043755 , UniProt:P97852

Relationship Links: InterPro:IN-FAMILY:IPR002198 , InterPro:IN-FAMILY:IPR002347 , InterPro:IN-FAMILY:IPR002539 , InterPro:IN-FAMILY:IPR003033 , InterPro:IN-FAMILY:IPR016040 , InterPro:IN-FAMILY:IPR029069 , PDB:Structure:1gz6 , PDB:Structure:1GZ6 , Pfam:IN-FAMILY:PF00106 , Pfam:IN-FAMILY:PF01575 , Pfam:IN-FAMILY:PF02036 , Prints:IN-FAMILY:PR00080 , Prints:IN-FAMILY:PR00081 , Prosite:IN-FAMILY:PS00061

Gene-Reaction Schematic: ?

Gene-Reaction Schematic

GO Terms:

Cellular Component: GO:0005777 - peroxisome [Jiang96]

Credits:
Created 24-Oct-2008 by Fulcher CA , SRI International


Enzymatic reaction of: (24R,25R)-3α,7α,24-trihydroxy-5β-cholestanoyl-CoA dehydrogenase (peroxisomal multifunctional enzyme type 2)

(24R,25R)-3α,7α,24-trihydroxy-5β-cholestanoyl CoA + NAD+ <=> 3α,7α-dihydroxy-24-oxo-5β-cholestanoyl CoA + NADH + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is favored in the direction shown.

In Pathways: bile acid biosynthesis, neutral pathway


Enzymatic reaction of: (24E)-3α,7α-dihydroxy-5β-cholest-24-enoyl-CoA hydratase (peroxisomal multifunctional enzyme type 2)

EC Number: 4.2.1.107

(24E)-3α,7α-dihydroxy-5β-cholest-24-enoyl-CoA + H2O <=> (24R,25R)-3α,7α,24-trihydroxy-5β-cholestanoyl CoA

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: bile acid biosynthesis, neutral pathway


Enzymatic reaction of: (24E)-3α,7α,12α-trihydroxy-5β-cholest-24-enoyl-CoA hydratase (peroxisomal multifunctional enzyme type 2)

Synonyms: 2-enoyl-CoA hydratase

EC Number: 4.2.1.107

(24R,25R)-3α,7α,12α,24-tetrahydroxy-5β-cholestanoyl CoA <=> (24E)-3α,7α,12α-trihydroxy-5β-cholest-24-enoyl-CoA + H2O

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction of enzyme catalysis.

This reaction is reversible. [Kurosawa01]

In Pathways: bile acid biosynthesis, neutral pathway

Summary:
The hydration reaction showed high diastereoselectivity for (24E)-3α,7α,12α-trihydroxy-5β-cholest-24-enoyl-CoA, or its dihydroxy form [Kurosawa01].


Enzymatic reaction of: (24R,25R)-3α,7α,12α,24-tetrahydroxy-5β-cholestanoyl-CoA dehydrogenase (peroxisomal multifunctional enzyme type 2)

Synonyms: (R)-3-hydroxyacyl-CoA dehydrogenase, D-3-hydroxyacyl-CoA dehydrogenase

(24R,25R)-3α,7α,12α,24-tetrahydroxy-5β-cholestanoyl CoA + NAD+ <=> 3α,7α,12α-trihydroxy-24-oxo-5-β-cholestanoyl CoA + NADH + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is favored in the direction shown.

In Pathways: bile acid biosynthesis, neutral pathway

Summary:
The dehydrogenation reaction showed high stereospecificity for (24R,25R)-3α,7α,12α,24-tetrahydroxy-5β-cholestanoyl CoA, or its trihydroxy form [Kurosawa01].


References

Bunya98: Bun-ya M, Maebuchi M, Kamiryo T, Kurosawa T, Sato M, Tohma M, Jiang LL, Hashimoto T (1998). "Thiolase involved in bile acid formation." J Biochem 123(2);347-52. PMID: 9538213

Haapalainen03: Haapalainen AM, Koski MK, Qin YM, Hiltunen JK, Glumoff T (2003). "Binary structure of the two-domain (3R)-hydroxyacyl-CoA dehydrogenase from rat peroxisomal multifunctional enzyme type 2 at 2.38 A resolution." Structure 11(1);87-97. PMID: 12517343

Jiang96: Jiang LL, Miyazawa S, Hashimoto T (1996). "Purification and properties of rat D-3-hydroxyacyl-CoA dehydratase: D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein." J Biochem 120(3);633-41. PMID: 8902630

Kurosawa01: Kurosawa T, Sato M, Nakano H, Fujiwara M, Murai T, Yoshimura T, Hashimoto T (2001). "Conjugation reactions catalyzed by bifunctional proteins related to beta-oxidation in bile acid biosynthesis." Steroids 66(2);107-14. PMID: 11146090

Qin97: Qin YM, Haapalainen AM, Conry D, Cuebas DA, Hiltunen JK, Novikov DK (1997). "Recombinant 2-enoyl-CoA hydratase derived from rat peroxisomal multifunctional enzyme 2: role of the hydratase reaction in bile acid synthesis." Biochem J 328 ( Pt 2);377-82. PMID: 9371691

Russell03: Russell DW (2003). "The enzymes, regulation, and genetics of bile acid synthesis." Annu Rev Biochem 72;137-74. PMID: 12543708

Xu96: Xu R, Cuebas DA (1996). "The reactions catalyzed by the inducible bifunctional enzyme of rat liver peroxisomes cannot lead to the formation of bile acids." Biochem Biophys Res Commun 221(2);271-8. PMID: 8619845


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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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