Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria

2021 ◽  
Author(s):  
Jinyue Ding ◽  
Rajesh Gumpena ◽  
Marc-Olivier Boily ◽  
Alexandre Caron ◽  
Oliver Chong ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Primary Hyperoxaluria ◽  
Glycolate Oxidase

Metabolism of Oxalate in Humans: A Potential Role Kynurenine Aminotransferase/Glutamine Transaminase/Cysteine Conjugate Betalyase Plays in Hyperoxaluria

2019 ◽  
Vol 26 (26) ◽  
pp. 4944-4963 ◽  
Author(s):  
Qian Han ◽  
Cihan Yang ◽  
Jun Lu ◽  
Yinai Zhang ◽  
Jianyong Li
Keyword(s):  
Cellular Localization ◽  
Structural Characteristics ◽  
Gene Mutations ◽  
Primary Hyperoxaluria ◽  
Glycolate Oxidase ◽  
Kynurenine Aminotransferase ◽  
Underlying Mechanisms ◽  
Urinary Oxalate Excretion ◽  
Glyoxylate Aminotransferase ◽  
Oxalate Metabolism

Hyperoxaluria, excessive urinary oxalate excretion, is a significant health problem worldwide. Disrupted oxalate metabolism has been implicated in hyperoxaluria and accordingly, an enzymatic disturbance in oxalate biosynthesis can result in the primary hyperoxaluria. Alanine-glyoxylate aminotransferase-1 and glyoxylate reductase, the enzymes involving glyoxylate (precursor for oxalate) metabolism, have been related to primary hyperoxalurias. Some studies suggest that other enzymes such as glycolate oxidase and alanine-glyoxylate aminotransferase-2 might be associated with primary hyperoxaluria as well, but evidence of a definitive link is not strong between the clinical cases and gene mutations. There are still some idiopathic hyperoxalurias, which require a further study for the etiologies. Some aminotransferases, particularly kynurenine aminotransferases, can convert glyoxylate to glycine. Based on biochemical and structural characteristics, expression level, and subcellular localization of some aminotransferases, a number of them appear able to catalyze the transamination of glyoxylate to glycine more efficiently than alanine glyoxylate aminotransferase-1. The aim of this minireview is to explore other undermining causes of primary hyperoxaluria and stimulate research toward achieving a comprehensive understanding of underlying mechanisms leading to the disease. Herein, we reviewed all aminotransferases in the liver for their functions in glyoxylate metabolism. Particularly, kynurenine aminotransferase-I and III were carefully discussed regarding their biochemical and structural characteristics, cellular localization, and enzyme inhibition. Kynurenine aminotransferase-III is, so far, the most efficient putative mitochondrial enzyme to transaminate glyoxylate to glycine in mammalian livers, which might be an interesting enzyme to look for in hyperoxaluria etiology of primary hyperoxaluria and should be carefully investigated for its involvement in oxalate metabolism.

The Identification of the Enzymes That Catalyse the Oxidation of Glyoxylate to Oxalate in the 100 000 g Supernatant Fraction of Human Hyperoxaluric and Control Liver and Heart Tissue

1973 ◽  
Vol 44 (3) ◽  
pp. 227-241 ◽  
Author(s):  
Dorothy A. Gibbs ◽  
R. W. E. Watts
Keyword(s):  
Lactate Dehydrogenase ◽  
Nicotinamide Adenine Dinucleotide ◽  
Liver Tissue ◽  
Primary Hyperoxaluria ◽  
Heart Tissue ◽  
Supernatant Fraction ◽  
Glycollate Oxidase ◽  
And Control ◽  
Oxalate Synthesis ◽  
Lactate Dehydrogenase Isoenzymes

1. The enzymic oxidation of glyoxylate to oxalate in the soluble (100 000 g supernatant) fraction of liver and heart tissue from a patient with primary hyperoxaluria and from a non-hyperoxaluric subject have been studied. 2. An oxidized nicotinamide—adenine dinucleotide (NAD+)-dependent and a non-NAD+-dependent oxidation of glyoxylate to oxalate were observed in the liver tissue from both sources. 3. Evidence is presented that lactate dehydrogenase has a major role in catalysing the reaction in both of the tissues studied. The non-NAD+-dependent oxidations which are catalysed by xanthine oxidase and glycollate oxidase in the liver are relatively unimportant, and they were not detected in the heart. 4. An enzyme that catalyses the oxidation of glycollate was also demonstrated in liver tissue. This had a different electrophoretic mobility from the lactate dehydrogenase isoenzymes. 5. These findings are discussed with particular reference to human primary hyperoxaluria in which excessive oxalate synthesis occurs.

scholarly journals BERGENIA CILIATA: ISOLATION OF ACTIVE FLAVONOIDS, GC-MS ANALYSIS, ADME STUDY AND INHIBITION ACTIVITY OF OXALATE SYNTHESIZING ENZYMES

2021 ◽  
pp. 34-46
Author(s):  
SHWETA R. GOPHANE ◽  
SAGAR R. JADHAO ◽  
PREETI B. JAMDHADE
Keyword(s):  
Lactate Dehydrogenase ◽  
Ethyl Acetate ◽  
Competitive Inhibition ◽  
Active Role ◽  
Glycolate Oxidase ◽  
Gas Chromatography Mass Spectrometry ◽  
Synthesis Methods ◽  
Lactate Dehydrogenase Activity ◽  
Chemical Structures ◽  
Ms Analysis

Objective: Bergenia ciliata (family-Saxifragaceae) is a well-known herb for kidney stone. The main objective of the study was the identification of flavonoids along with ADME profile. Another supportive objective was to check inhibition of enzymes which perform active role in oxalate synthesis. Methods: The hydromethanolic extract was fractionated by liquid-liquid extraction to obtain ethyl acetate and ethyl ether fractions. The chemical structures of the purified compounds were identified by gas chromatography-mass spectrometry. Results: A total of 12 volatile chemical compounds belonging to hydrocarbons, esters, alcohols, fatty acids, ketones, etc. were identified and characterized in ethyl acetate fraction through GC-MS analysis Fractions enriched in flavonoids showed glycolate oxidase and lactate dehydrogenase enzyme inhibition with IC50 value (µg/ml) 65.76 and 69.84 respectively. The kinetic behaviour of the extracts that inhibit the Glycolate oxidase and Lactate dehydrogenase activity was determined by the Lineweaver-Burk plot. The mode of inhibition of the studied plant extract was type of a non-competitive inhibition. ADMET screening of compounds successfully passed all the parameters of screening. Conclusion: On the basis of the results, it was found that Bergenia ciliata (rhizome) may serve as a novel and rich source of therapeutic compounds and it can be further explored for urolithiasis treatment purposes.

scholarly journals Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Tracy L McGregor ◽  
Karen A Hunt ◽  
Elaine Yee ◽  
Dan Mason ◽  
Paul Nioi ◽  
...  
Keyword(s):  
Healthy Adult ◽  
Primary Hyperoxaluria ◽  
Clinical Trial Data ◽  
Cellular Protein ◽  
Glycolate Oxidase ◽  
Human Populations ◽  
Protein Levels ◽  
Therapeutic Mechanisms ◽  
Hyperoxaluria Type

By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.

Comparison of the Amino Acid Sequence of L–Mandelate Dehydrogenase From Rhodotorula Graminis With Other L–2–Hydroxyacid Dehydrogenase Enzyme and its Primary Structure Prediction

2012 ◽  
Author(s):  
Rosli Md. Illias ◽  
Graeme A. Reid ◽  
Nadzarah A. Wahab
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Lactate Dehydrogenase ◽  
Primary Structure ◽  
Structure Prediction ◽  
Three Dimensional ◽  
Glycolate Oxidase ◽  
Dimensional Structure ◽  
Flavocytochrome B2 ◽  
Hansenula Anomala

Perbandingan struktur primer L(+)–mendalate dehydrogenase (L–MDH) daripada yis Rhodotorula graminis dengan protein lain di dalam bank data protein menunjukkan persamaan di antara protein ini dengan kumpulan enzim L–2–hidroksiasid dehidrogenase. LMDH daripada R. graminis mempamerkan kesamaan antara 26–42% kepada L–lactate dehidrogenase daripada Sacchomoryces cerevisiae, L–lactate dehidrogenase daripada Hansenula anomala, glikolat oksida daripada bayam, L–laktat dehidrogenase daripada Escherichia coli, LMDH daripada Psedomonas putida dan laktat–2 monooksigenase daripada Mycobakterium smegmatis. Asid amino yang penting secara strukturnya bagi LMDH diramalkan secara perbandingan dengan bahagian penting domain sitokram dan domain perlekatan FMN yang diperoleh daripada struktur tiga dimensi L–laktat dehidrogenase daripada Sacchoromyces cerevisiae. Kata kunci: L-MDH; Rhodotorula gramisis; L(+)-mandalate dehydrogenase; asid amino,flavocytochrome b2 A comparison of the primary structure or L–mandelate dehydrogenase (L–MDH) from Rhodotorula graminis with other proteins from the protein databank suggests that there is similarity between this protein and L–2–hydroxyacid dehydrogenase enzymes. R graminis LMDH exhibits 26–42% identity to L–lactate dehydrogenase from Saccharomyces cerevisiae, L–lactate dehydrogenase from Hansenula anomala, glycolate oxidase from spinach, L–lactate dehydrogenase from Escherichia coli, L–mandelate dehydrogenase from Pseudomonas putida and lactate–2–monooxygenase from Mycobacterium smegmatis. Structurally conserved amino acids are predicted from LMDH sequences corresponding to important regions of the cytochrome and FMN–binding domain defined from the known three–dimensional structure of the L–lactate dehyrogenase from Sacchoromyces cerevisiae. Key words: L-MDH; Rhodotorula graminis; L-mandelate dehydrogenase; amino acid;flavocytochrome b2

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