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evolution
aldose reductase (AKR1B1) is a member of the aldo-keto reductase superfamily
evolution
aldose reductase (ALR2) is a member of aldo-keto reductase superfamily
evolution
aldose reductase belongs to the aldoketo reductase superfamily, which includes several enzymes that catalyze oxidation and reduction reactions involved in various cellular processes
evolution
human aldose reductase (AKR1B1) is a member of the aldo-keto reductase superfamily, which consists of 15 families, 3 of which are mammalian containing the thirteen human aldo-keto reductase enzymes currently identified
evolution
the enzyme AKR1B1 belongs to the AKR1B subfamily
evolution
the enzyme AKR1B10 belongs to the AKR1B subfamily
evolution
the enzyme belongs to the aldo-keto reductase superfamily
evolution
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aldose reductase belongs to the aldoketo reductase superfamily, which includes several enzymes that catalyze oxidation and reduction reactions involved in various cellular processes
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evolution
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aldose reductase (ALR2) is a member of aldo-keto reductase superfamily
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malfunction
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aldose reductase inhibition prevents hypoxia-induced increase in hypoxia-inducible factor-1alpha and vascular endothelial growth factor by regulating 26 S proteasome-mediated protein degradation in colon cancer cells, molecular mechanism, overview. Inhibition of hypoxia-induced HIF-1 protein accumulation by enzyme inhibition is abolished in the presence of MG132, a potent inhibitor of the 26 S proteasome. Enzyme inhibition also prevents the hypoxia-induced inflammatory molecules such as Cox-2 and PGE2 and expression of extracellular matrix proteins such as MMP2, vimentin, uPAR, and lysyl oxidase 2, overview
malfunction
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enzyme inhibition prevents human colon cancer cell growth in culture as well as in nude mice xenografts. Inhibition of the enzyme also prevents angiogenic factors-induced invasion and migration of human umbilical vein endothelial cells and angiogenic factors-induced secretion/expression of ICAM, VCAM, MMP2, MMP9 and IL-6 in the cells, mechanisms, overview
malfunction
carnosine-propanals are converted to carnosine-propanols in the lysates of heart, skeletal muscle, and brain tissue from wild-type but not AR-null mice. In comparison with wild-type mice, the urinary excretion of carnosine-propanols is decreased in AR-null mice, overview
malfunction
enzyme deficiency-induced microglia/macrophages induce the M2 rather than the M1 response (classically activated pro-inflammatory (M1) or alternatively activated anti-inflammatory (M2) cells) and promote locomotion recovery after spinal cord injury in mice. In the in vitro experiments, microglia cell lines (N9 or BV2) are treated with the enzyme inhibitor fidarestat. Enzyme inhibition causes 4-hydroxynonenal accumulation, which induces the phosphorylation of the cAMP response element-binding. Enzyme deficiency causes NF-kappaB downregulation and CREB upregulation after spinal cord injury in mice
malfunction
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enzyme knockdown reduces the development of diet-induced liver fibrosis
malfunction
fidarestat inhibits acrolein-induced translocation of pro-apoptotic proteins Bax and Bad from cytosol to the mitochondria, and that of Bcl2 and BclXL from mitochondria to cytosol. Acrolein-induced cytochrome c release from mitochondria is also prevented by aldose reductase inhibition. The mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), stress-activated protein kinases/c-jun NH2-terminal kinases (SAPK/JNK) and p38MAPK, and c-jun are transiently activated in airway epithelial cells by acrolein in a concentration and time-dependent fashion, which are significantly prevented by enzyme aldose reductase inhibition. Enzyme inhibitors prevent acrolein-induced cytotoxicity in lung epithelial cells
malfunction
inhibition of AKR1B1 both prevents and reverses diabetic tissue injury that arises from the accumulation of sorbitol
malfunction
inhibition of the enzyme causes advanced glycation end products formation
malfunction
left ascending coronary artery ligation followed by 48 hrs of reperfusion is used as an ischemia-reperfusion (I/R) model, show a twofold increase in serum and myocardial triglycerides in cardiomyocyte-specific human AR (MHC-hAR) expressing mice compared to wild-type, whereas in global enzyme AR knockout mice, triglyceride levels are lower or comparable to wild-type subjected to I/R. Under basal conditions (in the absence of I/R), no changes triglyceride, but 2fold increased free fatty acids and a 2.5fold increase in PPARgamma expresssion occur in serum of MHC-hAR mice versus wild-type and the levels are comparable in wild-type and knockout mice, phenotypes, overview
malfunction
lipopolysacchride-induced RMG activation and migration into the inner nuclear layer or outer nuclear layer is largely prevented by enzyme inhibitors or in aldose reductase null mice, or is exacerbated in transgenic mice that over-express the enzyme
malfunction
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enzyme deficiency-induced microglia/macrophages induce the M2 rather than the M1 response (classically activated pro-inflammatory (M1) or alternatively activated anti-inflammatory (M2) cells) and promote locomotion recovery after spinal cord injury in mice. In the in vitro experiments, microglia cell lines (N9 or BV2) are treated with the enzyme inhibitor fidarestat. Enzyme inhibition causes 4-hydroxynonenal accumulation, which induces the phosphorylation of the cAMP response element-binding. Enzyme deficiency causes NF-kappaB downregulation and CREB upregulation after spinal cord injury in mice
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malfunction
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lipopolysacchride-induced RMG activation and migration into the inner nuclear layer or outer nuclear layer is largely prevented by enzyme inhibitors or in aldose reductase null mice, or is exacerbated in transgenic mice that over-express the enzyme
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metabolism
aldose reductase ALR2 acts in the polyol metabolic pathway
metabolism
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aldose reductase is the first enzyme in the polyol pathway and reduces glucose to sorbitol utilizing NADPH as a cofactor. Sorbitol is then metabolized to fructose by sorbitol dehydrogenase
metabolism
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aldose reductase is the key enzyme in the polyol pathway
metabolism
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aldose reductase plays key roles in the polyol pathway
metabolism
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aldose reductase, ALR2, and aldehyde reductase, ALR1, catalyse two following steps in the polyol pathway, overview
metabolism
ALR2 is the first and rate-limiting enzyme in the polyol pathway and reduces glucose to sorbitol utilizing NADPH as a cofactor. Sorbitol is then metabolized to fructose by sorbitol dehydrogenase
metabolism
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the enzyme catalyzes the first step in the polyol pathway of glucose metabolism
metabolism
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the enzyme is the first and rate-limiting enzyme in the polyol pathway where it catalyzes the reduction of glucose to sorbitol
metabolism
AKR1B1 functions in the polyol pathway as an NADPH-dependent enzyme, catalyzing the reduction of glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase
metabolism
AKR1B1 functions in the polyol pathway as an NADPH-dependent enzyme, catalyzing the reduction of glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase
metabolism
aldose reductase is the only enzyme responsible for reducing glucose to sorbitol in the polyol pathway of glucose metabolism
metabolism
ALR2 is the first rate-determining enzyme in the polyol pathway and catalyzes the reduction of glucose to sorbitol in the presence of NADPH as a cofactor. Sorbitol is in turn converted into fructose with accompanied reduction of NAD+ by sorbitol dehydrogenase. Under normal circumstances, glucose is predominantly converted to glucose-6-phosphate by hexokinase and then enters the glycolytic pathway, whereas only a small amount of glucose is metabolized through the polyol pathway due to a relatively low affinity of ALR2 for this substrate. During hyperglycemia, the polyol metabolic pathway is activated and the increased flux of glucose through the polyol pathway triggers the accumulation of sorbitol, which mainly happens in tissues demonstrating insulin-independent uptake of glucose, such as lens, kidney, retina, and peripheral nerves
metabolism
first and rate-limiting step of the polyol pathway
metabolism
first and rate-limiting step of the polyol pathway
metabolism
first and rate-limiting step of the polyol pathway. Distinct role for aldose reductase in lipid and retinoid metabolism through histone deacetylase 3 regulation and consequent derepression of PPARgamma and the retinoic acid receptor
metabolism
the enzyme is the first rate-determining enzyme in the polyol pathway and catalyzes the reduction of glucose to sorbitol in the presence of NADPH as a cofactor. Sorbitol is in turn converted into fructose with accompanied reduction of NAD+ by sorbitol dehydrogenase
metabolism
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aldose reductase is the only enzyme responsible for reducing glucose to sorbitol in the polyol pathway of glucose metabolism
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metabolism
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the enzyme catalyzes the first step in the polyol pathway of glucose metabolism
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metabolism
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ALR2 is the first rate-determining enzyme in the polyol pathway and catalyzes the reduction of glucose to sorbitol in the presence of NADPH as a cofactor. Sorbitol is in turn converted into fructose with accompanied reduction of NAD+ by sorbitol dehydrogenase. Under normal circumstances, glucose is predominantly converted to glucose-6-phosphate by hexokinase and then enters the glycolytic pathway, whereas only a small amount of glucose is metabolized through the polyol pathway due to a relatively low affinity of ALR2 for this substrate. During hyperglycemia, the polyol metabolic pathway is activated and the increased flux of glucose through the polyol pathway triggers the accumulation of sorbitol, which mainly happens in tissues demonstrating insulin-independent uptake of glucose, such as lens, kidney, retina, and peripheral nerves
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physiological function
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aldose reductase inhibition reduces sorbitol accumulation and cell death in ischemia-reperfusion injury in the retina, phenotype, overview
physiological function
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aldose reductase is involved in the polyol pathway, and regulates vascular smooth muscle cell proliferation by modulating G1/S phase transition of cell cycle. It prevents high glucose- or TNFalpha-induced vascular smooth muscle cell proliferation by accumulating the cells in the G1 phase
physiological function
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aldose reductase metabolizes both free and phospholipid aldehydes and exacerbates atherosclerotic lesion formation, increase in lesion area attributable to inhibition of the enzyme or deletion of the gene encoding the enzyme occurs in both male and female mice, phenotype of enzyme-deficient male and female mice with increases in arterial lesions, macrophage accumulation and interstitial fibrosis, and decreases smooth muscle cell content of arterial lesions, detailed overview
physiological function
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ALR2 is an enzyme of the polyol pathway, and of primary importance in the development of degenerative complications of diabetes mellitus, through its ability to reduce excess glucose into sorbitol with concomitant conversion of NADPH to NADP+
physiological function
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high sugar levels found in diabetic cataract cause the opacification of lenses by osmotic changes induced via the aldose reductase-mediated polyol pathway
physiological function
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inhibition of aldose reductase prevents growth factor-induced G1-S phase transition through the AKT/phosphoinositide 3-kinase/E2F-1 pathway in colon cancer cells. Inhibition of aldose reductasee prevents EGF- and bFGF-induced DNA binding activity and expression of E2F-1 in colon cancer cells, overview
physiological function
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the aldose reductase polyol pathway contributes to microvascular complications since the enzyme mediates vascular damage in response to hyperglycemia. Inhibition of AR reverses hyperglycemic suppression of RUNX2, and it also negatively regulates RUNX2-dependent vascular remodeling in an endothelial cell wounded monolayer assay, which is reversed by specific AR inhibition in hyperglycemia. RUNX2 and aldose reductase regulate glucose-activated endothelial cell wound healing
physiological function
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the enzyme and AGE-RAGE pathways, involving advanced glycation endproducts and their a soluble form of the chief signal transduction receptors, play central roles in the pathogenesis of vascular dysfunction in aging rats. Significant increases in aldose reductase expression and activity in aged rat vasculature linked to endothelial dysfunction may be mitigated, at least in part, via aldose reductase inhibitors and that aging-linked increased flux via aldose reductase generates advanced glycation endproducts, species which transduce endothelial injury consequent to their interaction with RAGE, the soluble form of the chief signal transduction receptors of advanced glycation products
physiological function
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the enzyme in involved in the hypoxia-induced colon cancer cells growth and invasion, overview
physiological function
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the enzyme is involved in oxidative stress signaling, it mediates colon cancer cell growth and proliferation involving angiogenic factors, such as VEGF- and FGF, overview
physiological function
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the enzyme is involved in sorbitol accumulation in red blood cells after peroxide, e.g. 2,2'-azobis(2-amidinopropane) hydrochloride and tert-butyl hydroperoxide, induced hemolysis, overview
physiological function
AKR1B10 is a tumor marker and displays high activity with the retinoic acid precursor all-trans-retinaldehyde and is induced in different types of cancer, notably in non-small cell lung and hepatocellular carcinomas
physiological function
aldehyde reductase exerts a detoxifying action and at the same time triggers a cell signaling cascade related to the antioxidant defense. The reduction of glucose catalyzed by aldose reductase, which is the first and rate-limiting step of the polyol pathway, is considered as one of the main deleterious events leading to the onset of diabetic complications. In fact, the accumulation of sorbitol and the concomitant reduction in the antioxidant's capability are significant factors leading to cell damage
physiological function
aldehyde reductase exerts a detoxifying action and at the same time triggers a cell signaling cascade related to the antioxidant defense. The reduction of glucose catalyzed by aldose reductase, which is the first and rate-limiting step of the polyol pathway, is considered as one of the main deleterious events leading to the onset of diabetic complications. In fact, the accumulation of sorbitol and the concomitant reduction in the antioxidant's capability are significant factors leading to cell damage
physiological function
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aldose reductase catalyzes the rate-limiting reduction of glucose to sorbitol with the aid of cofactor NADPH. The enzyme induces elevations on the level of CYP2E1 expression, reactive oxygen species, mRNA expression of TNF-alpha, and IL-6, confirmed in AML12 hepatocytes. The enzyme is involved in the development of methionine-choline-deficient diet-induced steatohepatitis in diabetic db/db mice, and plays a role in the development of diabetic complications. The enzyme alleviates the diet-induced (via methionine-choline-deficient (MCD) diet) liver inflammation and fibrosis in db/db mice, probably through dampening CYP2E1 mediated-oxidative stress and ameliorating the expression of pro-inflammatory cytokines
physiological function
aldose reductase is a stress response protein and a metabolic enzyme that is known to detoxify aldehydes besides reducing glucose to sorbitol in hyperglycemia. Aldose reductase regulates acrolein-induced cytotoxicity in small airway epithelial cells and prevents acrolein-induced DNA damage. Acrolein is a ubiquitous environmental pollutant that arises from incomplete combustion of plastic materials, forest fires, cigarette smoke, and pyrolyzed animal and vegetable fats. Acrolein causes apoptosis in number of cell types including keratinocytes, neutrophils and airway cells. Role of aldose reductase in acrolein cytotoxicity
physiological function
aldose reductase plays a critical role in mediating cardiovascular complications in diabetes, aging, and ischemia-reperfusion injury. Aldose reductase acts as a selective derepressor of PPARgamma and the retinoic acid receptor. Increased enzyme expression leads to histone deacetylase 3 degradation followed by increased PPARgamma signaling resulting in lipid accumulation in the heart. The enzyme also downregulates expression of nuclear corepressor complex cofactors including Gps2 and Tblr1, affecting activity of the nuclear corepressor complex itself. Though aldose reductase reduces HDAC3-corepressor complex formation, it specifically derepresses the retinoic acid receptor, but not other nuclear receptors such as the thyroid receptor and liver X receptor. Mechanisms by which hAR drives lipid accumulation in the heart, overview. The human enzyme competes with histone deacetylase 3 for the deacetylase containing domain, DAD, the nuclear receptor co-repressors NCOR1 and SMRT. Residue L289 of the human enzyme is essential for DAD interaction. DAD supplementation rescues the reduction in HDAC3 activity in the presence of recombinant aldose reductase
physiological function
aldose reductase regulates cytokine and chemokine production in the eye and mediates retinal microglia activation, role of the enzyme in RMG activation and migration in vivo, overview. Retinal microglia (RMG) are one of the major immune cells in charge of surveillance of inflammatory responses in the eye. In the absence of an inflammatory stimulus, RMG reside predominately in the ganglion layer and inner or outer plexiform layers. Under stress RMG become activated and migrate into the inner nuclear layer or outer nuclear layer. Activated RMG in cell culture secrete pro-inflammatory cytokines in a manner sensitive to downregulation by aldose reductase inhibitors. Aldose reductase expression in retinal microglia may contribute to the proinflammatory phenotypes common to various eye diseases such as uveitis and diabetic retinopathy
physiological function
aldose reductase regulates microglia/macrophages polarization through the cAMP response element-binding protein after spinal cord injury in mice, mechanism, overview
physiological function
aldose reductases are key enzymes in the detoxification of reactive aldehyde compounds like methylglyoxal and malondialdehyde
physiological function
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gene deletion of adhA reduces ethanol production by about 50%, whereas multiple gene deletions of all annotated alcohol dehydrogenases except adhA and adhE does not affect ethanol production. Deletion of adhA in wild-type reduces NADPH-linked ADH activity (acetaldehyde-reducing) by 93%
physiological function
increased reduction of glucose to sorbitol under hyperglycemic conditions is implicated in tissue injury and the progression of a wide variety of diabetic complications, including neuropathy and retinopathy
physiological function
lipid peroxidation generates unsaturated aldehydes, such as acrolein, that form conjugates with histidyl dipeptides. Carnosine-aldehyde conjugates form covalent adducts with proteins and are reduced by aldose reductase. Detoxification of carnosine-aldehyde by aldose reductase prevents protein carnosinylation. Aldose reductase prevents tissue injury due to aldehyde-carnosine conjugates. Role of aldose reductase as a critical regulator of protein carnosinylation and carnosine-mediated tissue protection, overview
physiological function
lipid peroxidation generates unsaturated aldehydes, such as acrolein, that form conjugates with histidyl dipeptides.Carnosine-aldehyde conjugates form covalent adducts with proteins and are reduced by aldose reductase. Detoxification of carnosine-aldehyde by aldose reductase prevents protein carnosinylation. Aldose reductase prevents tissue injury due to aldehyde-carnosine conjugates. Carnosine-propanals are converted to carnosine-propanols in the lysates of heart, skeletal muscle, and brain tissue from wild-type but not AR-null mice. Role of aldose reductase as a critical regulator of protein carnosinylation and carnosine-mediated tissue protection, overview
physiological function
aldose reductase interacts directly with tubulin and has greater affinity for 3-nitro-tyrosinated tubulin. Free 3-nitro-Tyr or Tyr prevents tubulin/aldose reductase complex formation and aldose reductase activation. The induction of microtubule formation by high concentrations of glucose and the consequent activation of aldose reductase in cultured cells can be inhibited by phenolic acid derivates that prevent the interaction tubulin/aldose reductase
physiological function
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aldose reductase regulates microglia/macrophages polarization through the cAMP response element-binding protein after spinal cord injury in mice, mechanism, overview
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physiological function
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aldose reductase regulates cytokine and chemokine production in the eye and mediates retinal microglia activation, role of the enzyme in RMG activation and migration in vivo, overview. Retinal microglia (RMG) are one of the major immune cells in charge of surveillance of inflammatory responses in the eye. In the absence of an inflammatory stimulus, RMG reside predominately in the ganglion layer and inner or outer plexiform layers. Under stress RMG become activated and migrate into the inner nuclear layer or outer nuclear layer. Activated RMG in cell culture secrete pro-inflammatory cytokines in a manner sensitive to downregulation by aldose reductase inhibitors. Aldose reductase expression in retinal microglia may contribute to the proinflammatory phenotypes common to various eye diseases such as uveitis and diabetic retinopathy
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physiological function
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gene deletion of adhA reduces ethanol production by about 50%, whereas multiple gene deletions of all annotated alcohol dehydrogenases except adhA and adhE does not affect ethanol production. Deletion of adhA in wild-type reduces NADPH-linked ADH activity (acetaldehyde-reducing) by 93%
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physiological function
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the enzyme is involved in sorbitol accumulation in red blood cells after peroxide, e.g. 2,2'-azobis(2-amidinopropane) hydrochloride and tert-butyl hydroperoxide, induced hemolysis, overview
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additional information
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inhibition of the enzyme prevents 4-hydroxy-trans-2-nonenal-and glutathione-4-hydroxy-trans-2-nonenal-induced E2F-1 expression
additional information
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inverse relationship between RUNX2 activity and AR expression, which is induced by hyperglycemia and supports a role for AR in the suppression of RUNX2 activity under hyperglycemic conditions
additional information
recombinant enzyme protein displays a significant level of antigenicity in BALB/c mice
additional information
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recombinant enzyme protein displays a significant level of antigenicity in BALB/c mice