PDBsum entry 4xzi

Oxidoreductase

PDB id: 4xzi

Contents

Protein chain

316 a.a.

Ligands

NAP

F49

Waters ×39

PDB id:

4xzi

Name:

Oxidoreductase

Title:

Crystal structure of human aldose reductase complexed with NADP+ and jf0049

Structure:

Aldose reductase. Chain: a. Synonym: ar,aldehyde reductase,aldo-keto reductase family 1 member b1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: akr1b1, aldr1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.45Å R-factor: 0.223 R-free: 0.290

Authors:

A.Cousido-Siah,F.X.Ruiz,A.Mitschler,M.Dominguez,A.R.De Lera,J.Farres, X.Pares,A.Podjarny

Key ref:

F.X.Ruiz et al. (2015). Structural Determinants of the Selectivity of 3-Benzyluracil-1-acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10. Chemmedchem, 10, 1989-2003. PubMed id: 26549844 DOI: 10.1002/cmdc.201500393

Date:

04-Feb-15 Release date: 18-Nov-15

Protein chain

P15121  (ALDR_HUMAN) -  Aldo-keto reductase family 1 member B1 from Homo sapiens

Seq: 316 a.a.

Struc: 316 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: E.C.1.1.1.21 - aldose reductase.
• Reaction:
  1. an alditol + NAD⁺ = an aldose + NADH + H⁺
  2. an alditol + NADP⁺ = an aldose + NADPH + H⁺

alditol + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = aldose + NADH + H(+)

alditol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = aldose + NADPH + H(+)

• Enzyme class 2: E.C.1.1.1.300 - NADP-retinol dehydrogenase.
• Reaction: all-trans-retinol + NADP⁺ = all-trans-retinal + NADPH + H⁺

all-trans-retinol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = all-trans-retinal + NADPH + H(+)

• Enzyme class 3: E.C.1.1.1.372 - D/L-glyceraldehyde reductase.
• Reaction:
  1. glycerol + NADP⁺ = L-glyceraldehyde + NADPH + H⁺
  2. glycerol + NADP⁺ = D-glyceraldehyde + NADPH + H⁺

glycerol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = L-glyceraldehyde + NADPH + H(+)

glycerol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = D-glyceraldehyde + NADPH + H(+)

• Enzyme class 4: E.C.1.1.1.54 - allyl-alcohol dehydrogenase.
• Reaction: allyl alcohol + NADP⁺ = acrolein + NADPH + H⁺

allyl alcohol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = acrolein + 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: 10.1002/cmdc.201500393

Chemmedchem 10:1989-2003 (2015)

PubMed id: 26549844

Structural Determinants of the Selectivity of 3-Benzyluracil-1-acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10.

F.X.Ruiz, A.Cousido-Siah, S.Porté, M.Domínguez, I.Crespo, C.Rechlin, A.Mitschler, �.�.R.de Lera, M.J.Martín, J.�.�.de la Fuente, G.Klebe, X.Parés, J.Farrés, A.Podjarny.

ABSTRACT

The human enzymes aldose reductase (AR) and AKR1B10 have been thoroughly explored in terms of their roles in diabetes, inflammatory disorders, and cancer. In this study we identified two new lead compounds, 2-(3-(4-chloro-3-nitrobenzyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (JF0048, 3) and 2-(2,4-dioxo-3-(2,3,4,5-tetrabromo-6-methoxybenzyl)-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (JF0049, 4), which selectively target these enzymes. Although 3 and 4 share the 3-benzyluracil-1-acetic acid scaffold, they have different substituents in their aryl moieties. Inhibition studies along with thermodynamic and structural characterizations of both enzymes revealed that the chloronitrobenzyl moiety of compound 3 can open the AR specificity pocket but not that of the AKR1B10 cognate. In contrast, the larger atoms at the ortho and/or meta positions of compound 4 prevent the AR specificity pocket from opening due to steric hindrance and provide a tighter fit to the AKR1B10 inhibitor binding pocket, probably enhanced by the displacement of a disordered water molecule trapped in a hydrophobic subpocket, creating an enthalpic signature. Furthermore, this selectivity also occurs in the cell, which enables the development of a more efficient drug design strategy: compound 3 prevents sorbitol accumulation in human retinal ARPE-19 cells, whereas 4 stops proliferation in human lung cancer NCI-H460 cells.