Purification and Characterization of a Membrane-bound Deglycating Enzyme (1-Deoxyfructosyl Alkyl Amino Acid Oxidase, EC 1.5.3) from a Pseudomonas sp. Soil Strain

Saxena, Amit; Saxena, Paresh; Monnier, Vincent M.

doi:10.1074/jbc.271.51.32803

Cited by 40 publications

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“…In doing so we found enzymes with "amadoriase" activity toward low molecular weight substrates in soil samples, first in Pseudomonas sp. (4) and later in Aspergillus fumigatus (5)(6)(7). The latter turned out to have similar properties with the enzyme first published by Horiuchi et al (8) under the name fructose amino acid oxidase (EC 1.5.3).…”

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confidence: 55%

“…Section 1734 solely to indicate this fact. The atomic coordinates and structure factors (codes 3DJD and 3DJE) 4 An Established Investigator of the American Heart Association. 5 The abbreviations used are: AGE, advanced glycation end product; FAOX, fructosamine oxidase; SeMet, selenomethionine; FSA, fructosyl thio-acetate; r.m.s.d., root mean square deviation; MSOX, monomeric sarcosine oxidase.…”

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confidence: 99%

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Crystal Structure of the Deglycating Enzyme Fructosamine Oxidase (Amadoriase II)

Collard

Zhang

Nemet

et al. 2008

Journal of Biological Chemistry

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Fructosamine oxidases (FAOX) catalyze the oxidative deglycation of low molecular weight fructosamines (Amadori products). These proteins are of interest in developing an enzyme to deglycate proteins implicated in diabetic complications. We report here the crystal structures of FAOX-II from the fungi Aspergillus fumigatus, in free form and in complex with the inhibitor fructosyl-thioacetate, at 1.75 and 1.6 Å resolution, respectively. FAOX-II is a two domain FAD-enzyme with an overall topology that is most similar to that of monomeric sarcosine oxidase. Active site residues Tyr-60, Arg-112 and Lys-368 bind the carboxylic portion of the fructosamine, whereas Glu-280 and Arg-411 bind the fructosyl portion. From structure-guided sequence comparison, Glu-280 was identified as a signature residue for FAOX activity. Two flexible surface loops become ordered upon binding of the inhibitor in a catalytic site that is about 12 Å deep, providing an explanation for the very low activity of FAOX enzymes toward protein-bound fructosamines, which would have difficulty accessing the active site. Structure-based mutagenesis showed that substitution of Glu-280 and Arg-411 eliminates enzyme activity. In contrast, modification of other active site residues or of amino acids in the flexible active site loops has little effect, highlighting these regions as potential targets in designing an enzyme that will accept larger substrates.Fructosamines are formed by condensation of glucose with the amino group of amino acids or proteins. Fructosamines are formed spontaneously, i.e. non-enzymatically, at a rate that depends on temperature, sugar anomerization rate, concentration, and turnover rate of the target proteins. In medicine, protein-bound fructosamines (also named glycated proteins) have attracted much attention since their formation is increased in diabetes and taken to be in part responsible for diabetic complications. Fructosamines are relatively unstable compounds and are precursors for advanced glycation end products (AGEs), 5 some of which cause proteins cross-linking, extracellular matrix stiffening, and activation of the receptor for AGEs (RAGEs) (1, 2). As an example, the fructosamine-derived lysine-arginine cross-link glucosepane is to date the single major cross-link known to accumulate in human collagen in diabetes and aging (3).Several years ago our laboratory initiated a search for deglycating enzymes in soil organisms with the goal of finding enzymes that could deglycate proteins. In doing so we found enzymes with "amadoriase" activity toward low molecular weight substrates in soil samples, first in Pseudomonas sp. (4) and later in Aspergillus fumigatus (5-7). The latter turned out to have similar properties with the enzyme first published by Horiuchi et al. (8) under the name fructose amino acid oxidase (EC 1.5.3). Considerable work has since been published on these enzymes, which we are referring to in this work under the generic name fructosamine oxidases (FAOX).In addition to FAOX enzymes, two different families o...

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confidence: 99%

Crystal Structure of the Deglycating Enzyme Fructosamine Oxidase (Amadoriase II)

Collard

Zhang

Nemet

et al. 2008

Journal of Biological Chemistry

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“…Fluorophore formation in the lens is believed to originate from non-enzymatic glycation of lens proteins. Hypothetically, the genetic influence could be caused by variations in the activity of enzymes modulating the glycated proteins as it has been observed in non-mammalian species [19,20]. A study showed that longevity in mammalian species was closely related to the rate of formation of advanced glycation end products and that species able to withstand the tissue damage caused by non-enzymatic glycation had longer life-spans [21].…”

Section: Discussionmentioning

confidence: 99%

Lens ageing as an indicator of tissue damage associated with smoking and non-enzymatic glycation - a twin study

et al. 2002

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Aims/hypothesis. With ageing the long-lived proteins of the human lens undergo denaturation by non-enzymatic glycation. The denaturated proteins are fluorescent, a property that can be assessed in vivo by fluorometry. Our aim was to examine the relative contribution of hereditary and environmental effects on the accumulation of fluorescent compounds in the lens. Methods. We examined 59 monozygotic and 55 dizygotic healthy twin pairs recruited from a populationbased register of twins. Lens autofluorescence was measured on the undilated eye. All subjects underwent an OGTT and information on smoking habits was obtained. The genetic and environmental effects were estimated by structural equation modelling. Results. Lens autofluorescence was related to age (R 2 =53%), current glucose homeostasis (R 2 =10%) and smoking habits (R 2 =10%). After adjusting for these factors, interindividual variation in lens autofluorescence was statistically attributable to hereditary factors by approximately 28% as well as shared environment by 58% and non-shared environment by 14%. The hereditary factor seems not to be linked to a genetic predisposition to diabetes. Conclusion/interpretation. The correlation in lens fluorescence was greater in monozygotic twins than dizygotic twins indicating a genetically predetermined susceptibility for the accumulation of fluorophores in the lens, the relative importance of which was found to increase with age. Since fluorophore formation in the lens is attributable to non-enzymatic glycation our results support that genetic characteristics to some degree determine the susceptibility to glycation related diabetes complications and ageing processes. [Diabetologia (2002[Diabetologia ( ) 45:1457[Diabetologia ( -1462 Keywords: Advanced glycation end products, ageing, crystalline lens, diabetes mellitus, environment, fluorometry, genetics, lens fluorescence, smoking, twins. The denaturation process leads to the formation of yellow, fluorescent, insoluble, high molecular weight protein aggregates [3]. In vitro [1] and in vivo studies in animals [4] and humans [5] have shown that the denaturation is caused by non-enzymatic glycation of lens proteins.The fluorescence of aged lens proteins can be assessed in vivo by non-invasive quantitative fluorometry. Lens autofluorescence is increased in diabetic subjects [6] and there is a relation between the long-term glycaemia and the value of lens fluorescence in huThe crystalline lens of the eye is an infolded ectodermal structure. Its function of forming an image on the retina requires an optically clear internal structure. This is obtained by specialized cells with a high content of densely packed proteins with no apparent turnover. With time these proteins are subject to physio-

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“…Amadori adducts, formed in the intermediate stages of AGEs formation can either be quenched by compounds such as aminoguanidine, or degraded enzymatically by enzymes such as amadoriase and human fructosamine-3-kinase, which belong to this group [149,150]. Amadoriases have not been detected in higher organisms [151,152].…”

Section: Anti-mg and Anti-ages Compoundsmentioning

confidence: 99%

Aging: Drugs to Eliminate Methylglyoxal, a Reactive Glucose Metabolite, and Advanced Glycation Endproducts

Dhar¹,

Desai²

2012

Pharmacology

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Purification and Characterization of a Membrane-bound Deglycating Enzyme (1-Deoxyfructosyl Alkyl Amino Acid Oxidase, EC 1.5.3) from a Pseudomonas sp. Soil Strain

Cited by 40 publications

References 27 publications

Crystal Structure of the Deglycating Enzyme Fructosamine Oxidase (Amadoriase II)

Crystal Structure of the Deglycating Enzyme Fructosamine Oxidase (Amadoriase II)

Lens ageing as an indicator of tissue damage associated with smoking and non-enzymatic glycation - a twin study

Aging: Drugs to Eliminate Methylglyoxal, a Reactive Glucose Metabolite, and Advanced Glycation Endproducts

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