Francesco Balestri1, Mario Cappiello2, Roberta Moschini2, Rossella Rotondo1, Marco Abate3, Antonella Del-Corso4, Umberto Mura2. 1. University of Pisa, Department of Biology, Biochemistry Unit, via San Zeno, 51, Pisa 56127, Italy. 2. University of Pisa, Department of Biology, Biochemistry Unit, via San Zeno, 51, Pisa 56127, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy. 3. University of Pisa, Department of Mathematics, via Buonarroti, 2, Pisa 56127, Italy. 4. University of Pisa, Department of Biology, Biochemistry Unit, via San Zeno, 51, Pisa 56127, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy. Electronic address: antonella.delcorso@unipi.it.
Abstract
BACKGROUND: Glucose is considered as one of the main sources of cell damage related to aldose reductase (AR) action in hyperglycemic conditions and a worldwide effort is posed in searching for specific inhibitors of the enzyme. This AR substrate has often been reported as generating non-hyperbolic kinetics, mimicking a negative cooperative behavior. This feature was explained by the simultaneous action of two enzyme forms acting on the same substrate. METHODS: The reduction of different aldoses and other classical AR substrates was studied using pure preparations of bovine lens and human recombinant AR. RESULTS: The apparent cooperative behavior of AR acting on glucose and other hexoses and pentoses, but not on tethroses, glyceraldehyde, 4-hydroxynonenal and 4-nitrobenzaldehyde, is generated by a partial nonclassical competitive inhibition exerted by the aldose hemiacetal on the reduction of the free aldehyde. A kinetic model is proposed and kinetic parameters are determined for the reduction of l-idose. CONCLUSIONS: Due to the unavoidable presence of the hemiacetal, glucose reduction by AR occurs under different conditions with respect to other relevant AR-substrates, such as alkanals and alkenals, coming from membrane lipid peroxidation. This may have implications in searching for AR inhibitors. The emerging kinetic parameters for the aldoses free aldehyde indicate the remarkable ability of the enzyme to interact and reduce highly hydrophilic and bulky substrates. GENERAL SIGNIFICANCE: The discovery of aldose reductase modulation by hemiacetals offers a new perspective in searching for aldose reductase inhibitors to be developed as drugs counteracting the onset of diabetic complications.
BACKGROUND:Glucose is considered as one of the main sources of cell damage related to aldose reductase (AR) action in hyperglycemic conditions and a worldwide effort is posed in searching for specific inhibitors of the enzyme. This AR substrate has often been reported as generating non-hyperbolic kinetics, mimicking a negative cooperative behavior. This feature was explained by the simultaneous action of two enzyme forms acting on the same substrate. METHODS: The reduction of different aldoses and other classical AR substrates was studied using pure preparations of bovine lens and human recombinant AR. RESULTS: The apparent cooperative behavior of AR acting on glucose and other hexoses and pentoses, but not on tethroses, glyceraldehyde, 4-hydroxynonenal and 4-nitrobenzaldehyde, is generated by a partial nonclassical competitive inhibition exerted by the aldose hemiacetal on the reduction of the free aldehyde. A kinetic model is proposed and kinetic parameters are determined for the reduction of l-idose. CONCLUSIONS: Due to the unavoidable presence of the hemiacetal, glucose reduction by AR occurs under different conditions with respect to other relevant AR-substrates, such as alkanals and alkenals, coming from membrane lipid peroxidation. This may have implications in searching for AR inhibitors. The emerging kinetic parameters for the aldoses free aldehyde indicate the remarkable ability of the enzyme to interact and reduce highly hydrophilic and bulky substrates. GENERAL SIGNIFICANCE: The discovery of aldose reductase modulation by hemiacetals offers a new perspective in searching for aldose reductase inhibitors to be developed as drugs counteracting the onset of diabetic complications.
Authors: Francesco Balestri; Giulio Poli; Carlotta Pineschi; Roberta Moschini; Mario Cappiello; Umberto Mura; Tiziano Tuccinardi; Antonella Del Corso Journal: Biomolecules Date: 2020-07-06
Authors: Francesco Balestri; Marinella De Leo; Carlo Sorce; Mario Cappiello; Luca Quattrini; Roberta Moschini; Carlotta Pineschi; Alessandra Braca; Concettina La Motta; Federico Da Settimo; Antonella Del-Corso; Umberto Mura Journal: J Enzyme Inhib Med Chem Date: 2019-12 Impact factor: 5.051
Authors: Blanca Colín-Lozano; Samuel Estrada-Soto; Fabiola Chávez-Silva; Abraham Gutiérrez-Hernández; Litzia Cerón-Romero; Abraham Giacoman-Martínez; Julio Cesar Almanza-Pérez; Emanuel Hernández-Núñez; Zhilong Wang; Xin Xie; Mario Cappiello; Francesco Balestri; Umberto Mura; Gabriel Navarrete-Vazquez Journal: Molecules Date: 2018-02-06 Impact factor: 4.411