PDBsum entry 4zfc

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4zfc

Contents

Protein chains

315 a.a.

Ligands

NAP ×2

GCZ ×2

Waters ×367

PDB id:

4zfc

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Crystal structure of akr1c3 complexed with glicazide

Structure:

Aldo-keto reductase family 1 member c3. Chain: a, b. Synonym: 17-beta-hydroxysteroid dehydrogenase type 5,17-beta-hsd 5,3- alpha-hsd type ii,brain,3-alpha-hydroxysteroid dehydrogenase type 2, 3-alpha-hsd type 2,chlordecone reductase homolog hakrb,dihydrodiol dehydrogenase 3,dd3,dihydrodiol dehydrogenase type i,ha1753,indanol dehydrogenase,prostaglandin f synthase,pgfs,testosterone 17-beta- dehydrogenase 5,trans-1,2-dihydrobenzene-1,2-diol dehydrogenase. Ec: 1.1.1.357,1.1.1.112,1.1.1.188,1.1.1.239,1.1.1.64,1.3.1.20.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: akr1c3. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.00Å R-factor: 0.175 R-free: 0.218

Authors:

Y.Zhao,X.Zhrng,X.Hu

Key ref:

Y.Zhao et al. (2015). In vitro inhibition of AKR1Cs by sulphonylureas and the structural basis. Chem Biol Interact, 240, 310-315. PubMed id: 26362498 DOI: 10.1016/j.cbi.2015.09.006

Date:

21-Apr-15 Release date: 25-Nov-15

Protein chains

P42330  (AK1C3_HUMAN) -  Aldo-keto reductase family 1 member C3 from Homo sapiens

Seq: 323 a.a.

Struc: 315 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.1.1.- - ?????
• Enzyme class 2: E.C.1.1.1.188 - prostaglandin-F synthase.
• Reaction: prostaglandin F2alpha + NADP⁺ = prostaglandin D2 + NADPH + H⁺

prostaglandin F2alpha (Bound ligand (Het Group name = NAP) corresponds exactly) + NADP(+) = prostaglandin D2 + NADPH + H(+)

• Enzyme class 3: E.C.1.1.1.210 - 3beta-(or 20alpha)-hydroxysteroid dehydrogenase.
• Reaction: 5alpha-androstane-3beta,17beta-diol + NADP⁺ = 17beta-hydroxy-5alpha- androstan-3-one + NADPH + H⁺

5alpha-androstane-3beta,17beta-diol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 17beta-hydroxy-5alpha- androstan-3-one + NADPH + H(+)

• Enzyme class 4: E.C.1.1.1.239 - 3alpha-(17beta)-hydroxysteroid dehydrogenase (NAD(+)).
• Reaction: testosterone + NAD⁺ = androst-4-ene-3,17-dione + NADH + H⁺

testosterone (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) + NAD(+) = androst-4-ene-3,17-dione + NADH + H(+)

• Enzyme class 5: E.C.1.1.1.357 - 3alpha-hydroxysteroid 3-dehydrogenase.
• Reaction:
  1. a 3alpha-hydroxysteroid + NADP⁺ = a 3-oxosteroid + NADPH + H⁺
  2. a 3alpha-hydroxysteroid + NAD⁺ = a 3-oxosteroid + NADH + H⁺

3alpha-hydroxysteroid + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 3-oxosteroid + NADPH + H(+)

3alpha-hydroxysteroid + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = 3-oxosteroid + NADH + H(+)

• Enzyme class 6: E.C.1.1.1.53 - 3alpha(or 20beta)-hydroxysteroid dehydrogenase.
• Reaction: androstan-3alpha,17beta-diol + NAD⁺ = 17beta-hydroxyandrostanone + NADH + H⁺

androstan-3alpha,17beta-diol + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = 17beta-hydroxyandrostanone + NADH + H(+)

• Enzyme class 7: 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) matches with 91.67% similarity) = estrone + NADH + H(+)

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

• Enzyme class 8: E.C.1.1.1.64 - testosterone 17beta-dehydrogenase (NADP(+)).
• Reaction: testosterone + NADP⁺ = androst-4-ene-3,17-dione + NADPH + H⁺

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

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: 10.1016/j.cbi.2015.09.006

Chem Biol Interact 240:310-315 (2015)

PubMed id: 26362498

In vitro inhibition of AKR1Cs by sulphonylureas and the structural basis.

Y.Zhao, X.Zheng, H.Zhang, J.Zhai, L.Zhang, C.Li, K.Zeng, Y.Chen, Q.Li, X.Hu.

ABSTRACT

Recent epidemiological studies show conflicting data for the first-line anti-diabetic sulphonylureas drugs in treating cancer progression in type II diabetes patients. How sulphonylureas promote or diminish tumor growth is not fully understood. Here, we report that seven sulphonylureas exhibit different in vitro inhibition towards AKR1Cs (AKR1C1, AKR1C2, AKR1C3), which are critical steroid hormone metabolism enzymes that are related to prostate cancer, breast cancer and endometrial diseases. Interactions of the sulphonylureas and AKR1Cs were analyzed by X-ray crystallography.