PDBsum entry 4cqm

Oxidoreductase

PDB id: 4cqm

Contents

Protein chains

(+ 2 more) 248 a.a.

(+ 2 more) 232 a.a.

Ligands

NAP ×16

GOL ×4

EDO ×8

ACT ×3

Waters ×806

PDB id:

4cqm

Name:

Oxidoreductase

Title:

Crystal structure of heterotetrameric human ketoacyl reductase complexed with NAD and NADP

Structure:

Estradiol 17-beta-dehydrogenase 8. Chain: a, e, h, i, l, m, p. Synonym: 17-beta-hydroxysteroid dehydrogenase 8,17-beta-hsd 8,3- oxoacyl-acyl-carrier-protein reductase, protein ke6,ke-6,really interesting new gene 2 protein, testosterone 17-beta-dehydrogenase 8, 3-ketoacyl reductase alpha subunit. Ec: 1.1.1.62, 1.1.1.239, 1.1.1.100. Engineered: yes. Carbonyl reductase family member 4.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: plyss rare.

Resolution:

2.34Å R-factor: 0.205 R-free: 0.236

Authors:

R.Venkatesan,S.K.Sahteli,L.O.Awoniyi,G.Jiang,P.Prus,A.J.Kastoniotis, J.K.Hiltunen,R.K.Wierenga,Z.Chen

Key ref:

R.Venkatesan et al. (2014). Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase. Nat Commun, 5, 4805. PubMed id: 25203508 DOI: 10.1038/ncomms5805

Date:

19-Feb-14 Release date: 10-Sep-14

Protein chains

Q92506  (DHB8_HUMAN) -  (3R)-3-hydroxyacyl-CoA dehydrogenase from Homo sapiens

Seq: 261 a.a.

Struc: 248 a.a.

Protein chains

Q8N4T8  (CBR4_HUMAN) -  3-oxoacyl-[acyl-carrier-protein] reductase from Homo sapiens

Seq: 237 a.a.

Struc: 232 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, D, E, H, I, L, M, P: E.C.1.1.1.239 - 3alpha-(17beta)-hydroxysteroid dehydrogenase (NAD(+)).
• Reaction: testosterone + NAD⁺ = androst-4-ene-3,17-dione + NADH + H⁺

testosterone + NAD(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = androst-4-ene-3,17-dione + NADH + H(+)

• Enzyme class 3: Chains A, D, E, H, I, L, M, P: E.C.1.1.1.62 - 17beta-estradiol 17-dehydrogenase.
• Reaction:
  1. 17beta-estradiol + NAD⁺ = estrone + NADH + H⁺
  2. 17beta-estradiol + NADP⁺ = estrone + NADPH + H⁺

17beta-estradiol + NAD(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = estrone + NADH + H(+)

• Enzyme class 4: Chains A, D, E, H, I, L, M, P: E.C.1.1.1.n12 - ?????
• Enzyme class 5: Chains B, C, F, G, J, K, N, O: E.C.1.1.1.100 - 3-oxoacyl-[acyl-carrier-protein] reductase.
• Reaction: a (3R)-hydroxyacyl-[ACP] + NADP⁺ = a 3-oxoacyl-[ACP] + NADPH + H⁺
• Enzyme class 6: Chains B, C, F, G, J, K, N, O: E.C.1.6.5.10 - Nadph dehydrogenase (quinone).
• Reaction: a quinone + NADPH + H⁺ = a quinol + NADP⁺
• Cofactor: Flavoprotein

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/ncomms5805

Nat Commun 5:4805 (2014)

PubMed id: 25203508

Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase.

R.Venkatesan, S.K.Sah-Teli, L.O.Awoniyi, G.Jiang, P.Prus, A.J.Kastaniotis, J.K.Hiltunen, R.K.Wierenga, Z.Chen.

ABSTRACT

Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory growth in yeast and mammalian embryonic survival. The human 3-ketoacyl-acyl carrier protein (ACP) reductase (KAR) of mtFAS is a heterotetrameric α2β2-assembly composed of 17β-hydroxysteroid dehydrogenase type-8 (HSD17B8, α-subunit) and carbonyl reductase type-4 (CBR4, β-subunit). Here we provide a structural explanation for the stability of the heterotetramer from the crystal structure with NAD(+) and NADP(+) bound to the HSD17B8 and CBR4 subunits, respectively, and show that the catalytic activity of the NADPH- and ACP-dependent CBR4 subunit is crucial for a functional HsKAR. Therefore, mtFAS is NADPH- and ACP dependent, employing the 3R-hydroxyacyl-ACP intermediate. HSD17B8 assists in the formation of the competent HsKAR assembly. The intrinsic NAD(+)- and CoA-dependent activity of the HSD17B8 subunit on the 3R-hydroxyacyl-CoA intermediates may indicate a role for this subunit in routing 3R-hydroxyacyl-CoA esters, potentially arising from the metabolism of unsaturated fatty acids, into the mitochondrial β-oxidation pathway.