Pathways of hepatic oxalate synthesis and their regulation.
Important features of hepatic oxalate synthesis remain uncertain despite its clinical significance. To clarify the terminal steps of the biosynthetic pathway and their modulation, we have examined oxalate and glyoxylate synthesis in vitro using isolated guinea pig peroxisomes and purified lactate dehydrogenase (LDH). Glycolate was rapidly oxidized to glyoxylate by isolated peroxisomes followed by a slower conversion of glyoxylate to oxalate. The glycolate oxidase (GO)-catalyzed conversion of glyoxylate to oxalate was strongly inhibited by physiological concentrations of glycolate and lactate. In contrast, the LDH-catalyzed conversion of glyoxylate to oxalate was only marginally affected by physiological concentrations of lactate and unaffected by physiological glycolate concentrations. This inhibition pattern suggests that LDH, not GO, catalyzes this conversion in vivo. Alanine inhibited oxalate synthesis by converting the bulk of the glyoxylate to glycine. On exposure to high alanine concentrations, however, inhibition was not complete and peroxisomes were able to convert sufficient glycolate to oxalate to account for daily endogenous oxalate production. NADH was a potent inhibitor of oxalate production by LDH by increasing glycolate formation from glyoxylate. Glycine was an ineffective source of glyoxylate, and an alkaline pH, a high-glycine concentration, and a prolonged incubation time were required to obtain a detectable synthesis. These results suggest that oxalate synthesis will be modulated by the metabolic state of the liver and resultant changes in NADH, lactate, and alanine levels.
Poore
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RE
Department of Urology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA.
Hurst
C H
CH
Assimos
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DG
Holmes
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RP
D000409:Alanine / Q000494:pharmacology; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D046508:Culture Techniques; D005260:Female; D005998:Glycine / Q000494:pharmacology; D006016:Glycolates / Q000378:metabolism; D006038:Glyoxylates / Q000378:metabolism; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000494:pharmacology; D019344:Lactic Acid / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008830:Microbodies / Q000378:metabolism; D009994:Osmolar Concentration; D010070:Oxalates / Q000378:metabolism*; D013997:Time Factors
D006016:Glycolates; D006038:Glyoxylates; D010070:Oxalates; C031149:glycolic acid; D019344:Lactic Acid; D000429:Alcohol Oxidoreductases; D007770:L-Lactate Dehydrogenase; C020821:glycollate oxidase; C031150:glyoxylic acid; D000409:Alanine; D005998:Glycine