LDHA (Lactate Dehydrogenase A Anaerobic Glycolysis & Oxalate Gene)
LDHA (lactate dehydrogenase A; HGNC:6535, NCBI Gene ID 3939) is a human locus mapped to chromosome band 11p15.1 that encodes lactate dehydrogenase M-subunit (332 aa; forms LDH-5 M4 homotetramer; EC 1.1.1.27). LDHA acts in anaerobic pyruvate-to-lactate reduction (NAD+ regeneration) & hepatic glyoxylate-to-oxalate oxidation, together with HAO1 (Peroxisomal Glycolate Oxidase Gene), HIF1A (Hypoxia-Inducible Factor 1-Alpha), and MYC Proto-Oncogene. Encodes the muscle/liver M-subunit of lactate dehydrogenase, catalyzing both anaerobic lactate production and the final step of hepatic oxalate synthesis.
Biallelic LoF causes glycogen storage disease XI (exertional myopathy); hepatic siRNA target of nedosiran (Rivfloza) in Primary Hyperoxaluria
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 8-exon gene on chromosome 11p15.1 containing hypoxia-inducible factor 1-alpha (HIF1A) and MYC response elements in its promoter, encoding a 332-amino-acid Rossmann-fold NAD(H)-binding oxidoreductase subunit.
Cellular & Tissue Expression Profile: Expressed at highest levels as the homotetrameric LDH-5 (M4) isozyme in glycolytic type II skeletal muscle fibers, hepatic hepatocytes, renal medulla, and hypoxic solid tumors (where it drives the Warburg effect).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: In skeletal muscle and glycolytic tissues, LDHA reduces pyruvate to L-lactate while regenerating cytosolic NAD+ required to sustain glyceraldehyde-3-phosphate dehydrogenase flux during anaerobic glycolysis; in hepatocyte cytosol, LDHA also catalyzes the terminal NAD+-dependent oxidation of two-carbon glyoxylate into non-metabolizable oxalate.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations in LDHA cause glycogen storage disease type XI (GSD XI), characterized by exertional muscle cramps, myoglobinuria upon intense anaerobic exercise, and psoriasiform skin lesions, but remarkably no hepatic dysfunction.
Therapeutic & Clinical Pharmacology: Because hepatic LDHA is the common final enzyme converting glyoxylate to oxalate across all three genetic forms of primary hyperoxaluria (PH1, PH2, and PH3), hepatocyte-selective GalNAc-conjugated siRNA nedosiran (Rivfloza, FDA-approved in 2023) silences liver LDHA mRNA without affecting skeletal muscle LDHA.