Urine 3-ketoglutaric acid

Glutaric acid occurs in plant and animal tissues and is found in the blood and urine. Ketoglutaric acid, found as an intermediate in the Krebs cycle, is used in dietary supplements to improve protein synthesis. ... 

Disposition in the Body. Readily absorbed after oral administration. It undergoes first-pass acetylation, the extent of which is genetically determined bioavailability 30 to 35% in slow acetylators, 10 to 16% in rapid acetylators. The major metabolites are 3-methyl-l,2,4-triazolo[3,4-a]phthalazine (MTP—the acetylation product) hydralazine pyruvic acid hydrazone (HPH) which is the major plasma metabolite 4-(2-acetylhydra-zino)phthalazin-l-one (A-AcHPZ) which is the major urinary metabolite 3-hydroxymethyl-1,2,4-triazolo[3,4-a]phthalazine (3-OHMTP). About 65% of a dose is excreted in the urine in 24 hours. In rapid acetylators, about 30% is excreted as A-AcHPZ and 10 to 30% as conjugated 3-OHMTP in slow acetylators, about 15 to 20% is excreted as A-AcHPZ and up to 10% as conjugated 3-OHMTP. Other metabolites include phthalazin-1-one (PZ), 1,2,4-triazolo[3,4-fl]phthalazine (TP), 9-hydroxy-MTP, phthalazine, tetrazolo[5,l-a]phthalazine, and hydrazones of hydralazine formed with acetone and a-ketoglutaric acid. About 10% of a dose is eliminated in the faeces. 

The concentration of a-ketoglutaric acid is much higher in urine than in blood (the reverse being generally true for pyruvic acid) (B18). 

I.I. Pyruvic Acid. Pyruvic acid is the predominant a-keto acid of human blood, whereas a-ketoglutaric acid predominates in human urine... 

The amount of pyruvic acid excreted in 24 hours has been found in recent works to lie between 2.5 and 11.5 mg (Z2, Z3, TA). As stated before, the amount of pyruvic acid in urine is lower than that of a-ketoglutaric acid Zelnicek (Z3) thus found 8.16 1.55mg/24 hours for pyruvic acid and 14.13 3.20mg/24 hours for a-ketoglutaric acid. 

Z3. Zelnicek, E., a-Ketoglutaric acid and pymvic acid in blood, cerebrospinal fluid and urine. Nature 184, 727 (1959). 

The D-2-HG acid concentration is elevated in urine, sometimes accompanied by increased 2-ketoglutaric acid excretion. Elevated concentrations of D-2-HGA in plasma and CSF, and total GABA in CSF were also reported [18-20]. 

Liao, J.C., Hoffman, N.E., Barboriak, J.J. and Roth, D.A. (1977), High performance liquid chromatography of pyruvic and a-ketoglutaric acids and its application to urine samples. Clin. Chem., 23,802. 

Another model substance that is used experimentally for the assessment of kidney function is para-aminohippuric acid (p-AH). p-AH appears in the urine not just by filtration but mainly by active secretion in the proximal tubule. This active transport process occurs in two steps (Figure 2.19a) In the first step, p-AH is exchanged at the basolateral membrane of the proximal tubule cell against a-ketoglutarate or other divalent anions. This exchange is driven by the membrane potential (the interior of the tubule cell is electrically negative relative to the outside, as is the case with essentially all cells). 

The blood alanine level is also always increased, sometimes markedly to about 2-4 times the normal value (L3, L6). This is presumably because the normal transamination of alanine to pyruvate, which requires a-ketoglutarate, is inhibited both by the excess of glutamine in the blood and by the drain on a-ketoglutarate. One other amino acid, camosine, has been found to be present in the plasma or in raised amounts in the urine, in those cases of hyperammonemia where it has been sought (LIO). There are no consistent changes in any of the other amino acids, including lysine, in the blood. 

Glyoxalate can be transaminated to glycine, reduced to glycolate, converted to a-hydroxy-/3-ketoadipate by reaction with a-ketoglutarate, or oxidized to oxalate and excreted in urine. The first three reactions require pyridoxal phosphate, NADH, and thiamine pyrophosphate, respectively. In humans, ascorbic acid (vitamin C) is a precursor of urinary oxalate (Chapter 38). Since calcium oxalate is poorly soluble in water, it can cause nephrolithiasis and nephrocalcinosis due to hyperoxaluria. 

Historical Development. Citric acid was the first of these acids to be identified in blood and urine. A few studies were later concerned with a-ketoglutaric and succinic acids in these biological fluids, until the development of chromatographic techniques allowed the determination of all acids of the tricarboxylic acid cycle, except the unstable ones (oxa-losuccinic and oxalacetic acids). Besides the chromatographic techniques, new enzymatic and fluorimetric methods have been described for some of these acids, including oxalacetic acid. 

More recently, Henning and Ammon (H19) described 10 aliphatic keto and aldehydic adds in normal urine. In addition to a-ketoglutaric, oxalacetic, pyruvic, glyoxylic, and a-ketoisocaproic acids, they found hydroxypyruvic, a-keto-y-methylthiobutyric, a-keto-fi-hydroxybutyric, a-keto-P-methylvaleric and a-keto-n-butyric acids, that is to say, the keto acids corresponding, respectively, to serine, methionine, threonine, isoleucine, and a-amino-n-butyric acid. They conclude that one finds in normal human urine the keto acids corresponding to all the amino adds normally present in urine, with the exception of those correspond-... 

In metabolic acidosis (p. 652) there is an increase in glutamine processing by the kidneys. Not all the excess NHj thus produced is released into the bloodstream or converted to urea some is excreted directly into the urine. In the kidney, the NHj forms salts with metabolic acids, facilitating their removal in the urine. Bicarbonate produced by the decarboxylation of a-ketoglutarate in the citric acid cycle can also serve as a buffer in blood plasma. Taken together, these effects of glutamine metabolism in the kidney tend to counteract acidosis. ... 

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