1.7 Å Structure of FR-1, a Fibroblast Growth Factor-Induced Member of the Aldo−Keto Reductase Family, Complexed with Coenzyme and Inhibitor

Wilson, D. Keith; Nakano, Taku; Petrash, J. Mark

doi:10.1021/bi9550253

Cited by 24 publications

(30 citation statements)

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“…7 The protein chain forms an ␣/␤ barrel with a cylindrical core of eight parallel ␤-strands surrounded by eight ␣-helices running antiparallel to the strands (Fig. 1).…”

Section: Results and Discussion Overall Structure Of Cho Reductase Anmentioning

confidence: 99%

Crystal structure of CHO reductase, a member of the aldo-keto reductase superfamily

Hyndman

et al. 2000

Proteins

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Chinese hamster ovary (CHO) re-ductase is an enzyme belonging to the aldo-keto reductase (AKR) superfamily that is induced by the aldehyde-containing protease inhibitor ALLN (In-oue, Sharma, Schimke, et al., J Biol Chem 1993;268: 5894). It shows 70% sequence identity to human aldose reductase (Hyndman, Takenoshita, Vera, et al., J Biol Chem 1997;272:13286), which is a target for drug design because of its implication in diabetic complications. We have determined the crystal structure of CHO reductase complexed with nicotin-amide adenine dinucleotide phosphate (NADP) to 2.4 A ˚ resolution. Similar to aldose reductase and other AKRs, CHO reductase is an / TIM barrel enzyme with cofactor bound in an extended confor-mation. All key residues involved in cofactor binding are conserved with respect to other AKR members. CHO reductase shows a high degree of sequence identity (91%) with another AKR member, FR-1 (mouse fibroblast growth factor-regulated protein), especially around the variable C-terminal end of the protein and has a similar substrate binding pocket that is larger than that of aldose reductase. However, there are distinct differences that can account for differences in substrate specificity. Trp111, which lies horizontal to the substrate pocket in all other AKR members is perpendicular in CHO reductase and is accompanied by movement of Leu300. This coupled with movement of loops A, B, and C away from the active site region accounts for the ability of CHO reductase to bind larger sub-strates. The position of Trp219 is significantly altered with respect to aldose reductase and appears to release Cys298 from steric constraints. These studies show that AKRs such as CHO reductase are excellent models for examining the effects of subtle changes in amino acid sequence and alignment on binding and catalysis. Proteins 2000;38:41-48. 2000 Wiley-Liss, Inc.

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“…7 The protein chain forms an ␣/␤ barrel with a cylindrical core of eight parallel ␤-strands surrounded by eight ␣-helices running antiparallel to the strands (Fig. 1).…”

Section: Results and Discussion Overall Structure Of Cho Reductase Anmentioning

confidence: 99%

Crystal structure of CHO reductase, a member of the aldo-keto reductase superfamily

Hyndman

et al. 2000

Proteins

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“…monosaccharides, steroids, prostaglandins, aliphatic aldehydes and xenobiotic compounds). These aldoketo reductases play an important role in detoxification of naturally occurring carbonyls [36]. Aldose reductase is one of the best studied aldoketo reductases.…”

Section: Discussionmentioning

confidence: 99%

Further Characterization of a Rat Hepatoma‐Derived Aldose‐Reductase‐Like Protein

Zeindl‐Eberhart

Jungblut

Otto

et al. 1997

European Journal of Biochemistry

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A protein detected in N-methyl-N-nitrosourea-initiated rat hepatomas by two-dimensional electrophoresis at 35 kDdpI 7.4 was identified in a previous study by internal amino acid micro sequencing as an aldose-reductase-like protein [Zeindl-Eberhart, E., Jungblut, P. R., Otto, A. & Rabes, H. M. (1994) Identification of tumor-associated protein variants during rat hepatocarcinogenesis, J. Biol. Chem. 269, 14 589-14 5941. Two-dimensional electrophoresis of rat lens proteins revealed a spot at 37 kDa/pI 6.8 that showed a high degree of identity (98.5%) with rat lens aldose reductase after amino acid sequencing and 80% sequence identity to the rat-hepatoma-derived aldose-reductase-like protein. This suggests that hepatomaderived aldose-reductase-like protein and rat lens aldose reductase are related proteins encoded by different genes. A different expression profile of these proteins was found in various rat organs. Rat lens aldose reductase is present, in addition to in lens, in heart, brain, muscle, lung, duodenum, kidney, spleen and bone marrow, while the hepatoma-derived aldose-reductase-like protein is found preferentially in hepatomas and in embryonic liver. Though different in organ expression, an identical response was found for both proteins after stimulation with fibroblast growth factor-1 and after exposure to increased glucose concentrations. Since rat hepatoma-derived aldose-reductase-like protein is expressed in embryonic, but not in adult liver, it is assumed that it is expressed in hepatomas as a functionally active embryonal type of aldose reductase during hepatocarcinogenesis. Immunohistochemistry revealed that the hepatomaderived aldose-reductase-like protein is expressed already in the preneoplastic stage of hepatocarcinogenesis and might potentially serve as a marker enzyme in early hepatic neoplasia.Keywords: two-dimensional electrophoresis ; rat hepatoma; aldose-reductase-like protein.Misprogramming of genetic information in cancer may lead to quantitative andor qualitative protein alterations. Such changes can be studied by high resolution two-dimensional electrophoresis [ 1-31, in combination with ultrasensitive silver staining [4, 51. Two-dimensional electrophoresis has successfully been used to detect tumor associated proteins in chemically induced rat hepatomas [6-121.We detected previously several protein variants in N-methyl-N-nitrosourea-induced rat hepatomas by two-dimensional electrophoresis [ I l l and identified one of these variants (spot 17) by amino acid sequencing as an enzyme apparently related to rat lens aldose reductase (AR) [13]. In a different system, NIH 3T3 mouse fibroblasts, it was shown that fibroblast growth factor-I (FGF-I) induced temporarily an increased level of FGF-1-regulated (FR-1) mRNA [14]. The amino acid sequence deduced from FR-1 mRNA revealed 97% sequence identity [I41 to the rat hepatoma-derived AR-like protein of chemically induced hepatomas [ 131. These findings of putative relations between rat hepatoma-derived AR-like protein, rat lens AR and FR-1 prot...

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“…Recent subatomic resolution AKR1B1-inhibitor structures suggest the possibility that the spirohydantoin inhibitors bind in a neutral state and then become charged inside the active site pocket (Podjarny et al, 2004). ARK1B inhibitors make multiple contacts with mostly hydrophobic active site residues of the protein active site via a significant number of van der Waals contacts (Wilson et al, 1995;Wilson et al, 1993;Steuber et al, 2008). The active site of the enzyme is capable of large conformational changes to accommodate the inhibitor and thus offer a high-efficiency template for binding to inhibitors complementary to the active site.…”

Section: Iii) Inhibitorsmentioning

confidence: 99%

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Barski

Tipparaju

Bhatnagar

2008

Drug Metabolism Reviews

442

340

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The Aldo-Keto Reductase (AKR) superfamily comprises of several enzymes that catalyze redox transformations involved in biosynthesis, intermediary metabolism and detoxification. Substrates of the family include glucose, steroids, glycosylation end products, lipid peroxidation products, and environmental pollutants. These proteins adopt a (β/α) 8 barrel structural motif interrupted by a number of extraneous loops and helixes that vary between proteins and bring structural identity to individual families. The human AKR family differs from the rodent families. Due to their broad substrate specificity, AKRs play an important role in the Phase II detoxification of a large number of pharmaceuticals, drugs, and xenobiotics.

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1.7 Å Structure of FR-1, a Fibroblast Growth Factor-Induced Member of the Aldo−Keto Reductase Family, Complexed with Coenzyme and Inhibitor

Cited by 24 publications

References 0 publications

Crystal structure of CHO reductase, a member of the aldo-keto reductase superfamily

Crystal structure of CHO reductase, a member of the aldo-keto reductase superfamily

Further Characterization of a Rat Hepatoma‐Derived Aldose‐Reductase‐Like Protein

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

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