What is the difference between uric acid and lactic acid

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Chartrand: Proc. Hartmann: in preparation Google Scholar. Hartmann, H. Hoos, H. Perheentupa, K. Woods, H. Alberti: Lancet 11, Google Scholar. Hartmann 1 H. Zentrum der Biol. Frankfurt Deutschland. Personalised recommendations. Cite chapter How to cite? ENW EndNote. Buy options. We now demonstrate that autosomal recessive gout with hyperuricemia and underexcretion of uric acid can be caused by a mutation in lactate dehydrogenase D LDHD , resulting in excess blood d -lactate that is excreted in exchange for reabsorbed uric acid.

Clinical characterization. Consanguineous Bedouin-Israeli kindred presented with autosomal recessive hyperuricemia Figure 1A. All affected adults were clinically diagnosed with gout arthropathy and described classic symptoms of the disease, including both upper- and lower-limb joint pain, particularly in small joints of the palms and toes, with acute gout flares every 3 to 6 months more often in some that were aggravated by meat consumption.

All patients were treated with colchicine and allopurinol, had normal blood creatinine levels with no other evidence of chronic kidney disease or cardiovascular sequelae, and were otherwise healthy. Pedigree and plasma uric acid measurements of a kindred affected with gout. A Diagram of the studied kindred.

Black squares and circles denote affected kindred, white squares and circles denote unaffected kindred, and double black lines indicate consanguinity. B Average plasma uric acid concentrations in individuals of the studied kindred who were WT, heterozygous, or homozygous for the LDHD mutation. Error bars indicate the SD. Average plasma uric acid levels were To assess renal handling of uric acid, we performed urine analyses on several of the affected individuals.

Molecular genetic studies. We identified a single homozygous locus of approximately 12 Mbp on chromosome 16 between rs and rs that was shared between all affected family members and none of the healthy ones maximal logarithm of the odds [LOD] score of 4. Following the variant filtration cascade see Methods , only a single homozygous variant within the genomic locus identified through linkage analysis was found to be shared by both individuals: c.

We performed whole-genome sequencing on one of the affected individuals III:7 to exclude any insertions or deletions in noncoding regions of the homozygous locus identified in the linkage analysis. Sanger sequencing validated the segregation of the mutation in the family, as expected for autosomal recessive heredity Figure 2A. Mutation screening using restriction analysis, which we performed on 92 unaffected members of the particularly highly inbred tribe of the studied kindred, revealed 7 heterozygous carriers of the mutation and no homozygotes not shown.

LDHD mutation verification, conservation, and structural prediction. The c. The black box marks the highly conserved arginine residue altered by the c. The symbols show conservation: asterisk indicates identical; colon indicates strongly similar; period indicates weakly similar; blank indicates no similarity. The 2 monomers of d -lactate dehydrogenase are shown in light blue and dark green; FAD is represented as sticks in pink; the site of the p.

D Zoom-in on the residues comprising the catalytic pocket of 3PM9 yellow and an overlay of the model for d -lactate dehydrogenase with its homologous residues light blue. FAD is presented as sticks in pink; the site of the RW substitution is shown in orange; the dashed lines indicate hydrogen bonds; nitrogen is labeled in blue; and oxygen is labeled in red.

Normally, lactic acid is found in humans entirely as l -lactate, as mammalian cells almost exclusively produce this form However, d -lactate can be generated in miniscule concentrations via the glyoxalase pathway, which facilitates degradation of methylglyoxal, a byproduct of several fundamental metabolic processes including glycolysis, amino acid degradation, and ketone body catabolism.

In this pathway, methylglyoxal is converted to d -lactate following a series of enzymatic reactions. The final step of the pathway is the d -lactate-dehydrogenase—dependent conversion of d -lactate to pyruvate 17 , which may then serve as a substrate in a variety of downstream metabolic pathways 18 , The LDHD p.

RW missense mutation putatively alters a highly conserved arginine residue to tryptophan Figure 2B. This hypothesis is strongly supported by a recent parallel independent study that proved that 2 separate loss-of-function mutations in the human LDHD gene, p. WC and p. TM, caused elevated urinary excretion and plasma concentrations of d -lactate Both mutations alter amino acid residues located in proximity to the residues comprising the putative catalytic pocket of the protein and to the arginine residue altered by the novel p.

RW mutation. Protein localization analyses. It was previously shown that d -lactate dehydrogenase localizes to mitochondria in mammalian cells To verify that in humans the protein is indeed mitochondrial and to determine whether the mutation affected the subcellular localization of the protein, we transfected HEK cells with WT and p.

We then isolated the mitochondria and cytosolic fractions of the transfected cells and subsequently performed Western blot analysis.

Both the WT and p.