A superfamily of NADPH-dependent reductases in eukaryotes and prokaryotes.

Aldose reductase (AR) is implicated in some of the disabling complications of diabetes, including neuropathy, retinopathy and cataracts. Our studies are aimed at further clarifying the role of AR in diabetes and facilitating the design of new classes of potent, specific AR inhibitors by gaining an understanding of the protein structure of AR. To this end, we have determined the complete protein sequence of rat lens AR using cDNA analysis and primer extension of mRNA. By comparing protein sequences, we have found that the structural relatedness (41% to 57%) among the vertebrate proteins, aldose reductase, aldehyde reductase, prostaglandin F synthase and the frog lens protein rho-crystallin can now be extended to prokaryotes by the inclusion of Corynebacterium 2,5-diketo-D-gluconate reductase. This more distantly related protein shares 30-40% identity with the vertebrate enzymes. Sequence alignments reveal that 18% of the amino acids are completely conserved in all members of the superfamily, many of them in clusters, suggesting that they mark important structural features such as the nucleotide binding site and substrate binding site. rho-Crystallin, which is structurally related to this superfamily of NADPH-dependent reductases, does not appear to reduce PGH2, PGD2, xylose or glyceraldehyde to any appreciable extent. It does, however, bind NADPH.

[1]  N. Sharpless,et al.  Aldose reductase inhibitors: a potential new class of agents for the pharmacological control of certain diabetic complications. , 1985, Journal of medicinal chemistry.

[2]  S. Nakanishi,et al.  Structural similarity of bovine lung prostaglandin F synthase to lens epsilon-crystallin of the European common frog. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Flynn,et al.  Properties of the nicotinamide adenine dinucleotide phosphate-dependent aldehyde reductase from pig kidney. Amino acid composition, reactivity of cysteinyl residues, and stereochemistry of D-glyceraldehyde reduction. , 1975, The Journal of biological chemistry.

[4]  L. Levine,et al.  Decreased levels of an inhibitor of prostaglandin E 9-ketoreductase activity in chick dystrophic breast muscle , 1976, Nature.

[5]  T. Hohman,et al.  Characterization of mRNA and genes for aldose reductase in rat. , 1988, Biochemical and biophysical research communications.

[6]  R. L. Felsted,et al.  Mammalian carbonyl reductases. , 1980, Drug metabolism reviews.

[7]  J. V. Miller,et al.  Purification and characterization of 2,5-diketo-D-gluconate reductase from Corynebacterium sp. , 1987, The Journal of biological chemistry.

[8]  T. Shinohara,et al.  Aldose reductase and ϱ‐crystallin belong to the same protein superfamily as aldehyde reductase , 1987, FEBS letters.

[9]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[10]  K. Watanabe,et al.  Enzymatic formation of prostaglandin F2 alpha from prostaglandin H2 and D2. Purification and properties of prostaglandin F synthetase from bovine lung. , 1985, The Journal of biological chemistry.

[11]  B. Wermuth.  Aldo-keto reductases. , 1985, Progress in clinical and biological research.

[12]  K. Gabbay,et al.  Mechanism of development and possible prevention of sugar cataracts. , 1972, Israel journal of medical sciences.

[13]  K. Watanabe,et al.  Stereospecific conversion of prostaglandin D2 to (5Z,13E)-(15S)-9 alpha-11 beta,15-trihydroxyprosta-5,13-dien-1-oic acid (9 alpha,11 beta-prostaglandin F2) and of prostaglandin H2 to prostaglandin F2 alpha by bovine lung prostaglandin F synthase. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[14]  B. Wermuth,et al.  Primary structure of aldehyde reductase from human liver. , 1987, Progress in clinical and biological research.

[15]  J. A. Cromlish,et al.  Pig muscle aldehyde reductase. Identity of pig muscle aldehyde reductase with pig lens aldose reductase and with the low Km aldehyde reductase of pig brain and pig kidney. , 1983, The Journal of biological chemistry.

[16]  B. Wermuth.  Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase. , 1981, The Journal of biological chemistry.

[17]  B. Wermuth,et al.  Purification and properties of NADPH-dependent aldehyde reductase from human liver. , 1977, The Journal of biological chemistry.

[18]  T. Flynn.  Aldehyde reductases: monomeric NADPH-dependent oxidoreductases with multifunctional potential. , 1982, Biochemical pharmacology.

[19]  K. Skryabin,et al.  A novel type of crystallin in the frog eye lens , 1984, FEBS letters.

[20]  R. Lazarus,et al.  What Makes a Good Computer Device? , 1985, Science.

[21]  J. Geliebter,et al.  Mitotic recombination in germ cells generated two major histocompatibility complex mutant genes shown to be identical by RNA sequence analysis: Kbm9 and Kbm6. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Xenobiotic Ketone Reductase.  Purification and Properties of an NADPH-dependent Carbonyl Reductase from Human Brain , 1980 .

[23]  M. Kozak,et al.  Point mutations close to the AUG initiator codon affect the efficiency of translation of rat preproinsulin in vivo , 1984, Nature.

[24]  M. Kozak.  Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. , 1984, Nucleic acids research.

[25]  C. Sheaff,et al.  Physical and kinetic properties of homogenous bovine lens aldose reductase. , 1976, The Journal of biological chemistry.

[26]  N. Bachur.  Cytoplasmic aldo-keto reductases: a class of drug metabolizing enzymes. , 1976, Science.

[27]  W. W. Jong,et al.  The enzyme lactate dehydrogenase as a structural protein in avian and crocodilian lenses , 1987, Nature.

[28]  J. Piatigorsky,et al.  Recruitment of enzymes as lens structural proteins. , 1987, Science.

[29]  Michael G. Rossmann,et al.  Chemical and biological evolution of a nucleotide-binding protein , 1974, Nature.

[30]  T. Flynn,et al.  A comparative study of the tissue and species distribution of NADPH-dependent aldehyde reductase. , 1978, Comparative biochemistry and physiology. B, Comparative biochemistry.

[31]  J. Kinoshita,et al.  The Pharmacology of Aldose Reductase Inhibitors , 1985 .

[32]  P. Terpstra,et al.  Prediction of the Occurrence of the ADP-binding βαβ-fold in Proteins, Using an Amino Acid Sequence Fingerprint , 1986 .

[33]  D. Murphy,et al.  Chicken muscle aldose reductase: purification, properties and relationship to other chicken aldo/keto reductases. , 1986, The International journal of biochemistry.

[34]  J. Garnier,et al.  Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. , 1978, Journal of molecular biology.