PDBsum entry 2inz

Oxidoreductase

PDB id: 2inz

Contents

Protein chain

315 a.a. *

Ligands

NAP

OHP

Waters ×131

* Residue conservation analysis

PDB id:

2inz

Name:

Oxidoreductase

Title:

Crystal structure of aldose reductase complexed with 2- hydroxyphenylacetic acid

Structure:

Aldose reductase. Chain: a. Synonym: ar, aldehyde reductase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: akr1b1, aldr1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.95Å R-factor: 0.228 R-free: 0.259

Authors:

D.H.T.Harrison,E.Pape,E.Carlson,J.M.Brownlee

Key ref:

J.M.Brownlee et al. (2006). Structural and thermodynamic studies of simple aldose reductase-inhibitor complexes. Bioorg Chem, 34, 424-444. PubMed id: 17083960 DOI: 10.1016/j.bioorg.2006.09.004

Date:

09-Oct-06 Release date: 21-Nov-06

Protein chain

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

Seq: 316 a.a.

Struc: 315 a.a.

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: 10.1016/j.bioorg.2006.09.004

Bioorg Chem 34:424-444 (2006)

PubMed id: 17083960

Structural and thermodynamic studies of simple aldose reductase-inhibitor complexes.

J.M.Brownlee, E.Carlson, A.C.Milne, E.Pape, D.H.Harrison.

ABSTRACT

The competitive inhibition constants of series of inhibitors related to phenylacetic acid against both wild-type and the doubly mutanted C298A/W219Y aldose reductase have been measured. Van't Hoff analysis shows that these acids bind with an enthalpy near -6.8 kcal/mol derived from the electrostatic interactions, while the 100-fold differences in binding affinity appear to be largely due to entropic factors that result from differences in conformational freedom in the unbound state. These temperature studies also point out the difference between substrate and inhibitor binding. X-ray crystallographic analysis of a few of these inhibitor complexes both confirms the importance of a previously described anion binding site and reveals the hydrophobic nature of the primary binding site and its general plasticity. Based on these results, N-glycylthiosuccinimides were synthesized to demonstrate their potential in studies that probe distal binding sites. Reduced alpha-lipoic acid, an anti-oxidant and therapeutic for diabetic complications, was shown to bind aldose reductase with a binding constant of 1 microM.