This article was accepted into the corpus but its outbound wikilinks were never NER-processed — typical at the deepest BFS hop or when the run's entity cap was reached. No expansion funnel to show.
| LDHA | |
|---|---|
| Name | Lactate dehydrogenase A |
| Ec number | 1.1.1.27 |
| Gene | LDHA |
| Synonyms | LDH-A, M-subunit, LDH-M |
LDHA LDHA is a protein-coding gene that encodes the A (muscle) subunit of lactate dehydrogenase, a key enzyme in anaerobic metabolism and cellular redox balance. It participates in pyruvate-to-lactate interconversion and has important roles in hypoxia responses, metabolic reprogramming in proliferative tissues, and clinical contexts including oncology and inherited metabolic disorders. High-resolution structures, genetic studies, and pharmacological efforts have characterized its biochemical properties and therapeutic potential.
The human LDHA gene resides on chromosome 11 and encodes a ~332-amino-acid polypeptide that assembles into homo- or heterotetramers. X-ray crystallography and cryo-EM studies reveal an active-site cleft that binds NADH and pyruvate with conserved catalytic residues and a Rossmann-like NAD-binding fold. Comparative mapping links the locus to nearby genes studied in genomic consortia such as the Human Genome Project, International HapMap Project, and datasets from the 1000 Genomes Project. Structural studies reference crystals solved by groups at institutions like the European Molecular Biology Laboratory and University of Oxford, and models validated against data from the Protein Data Bank.
The enzyme catalyzes the reversible reduction of pyruvate to lactate with concomitant oxidation of NADH to NAD+, operating near equilibrium in cytosolic metabolism. Mechanistic proposals derive from kinetic analyses performed in laboratories affiliated with the Max Planck Society, Massachusetts Institute of Technology, and Stanford University. Key steps include hydride transfer from NADH to the carbonyl carbon of pyruvate and proton donation by an active-site histidine; transition-state stabilization has been probed using site-directed mutants generated in facilities like the Sloan Kettering Institute and Johns Hopkins University. Classic enzymology techniques from the Royal Society-affiliated groups and methodologies described in texts from the American Chemical Society underpin current catalytic models.
Expression is developmentally and tissue-regulated, with higher levels in skeletal muscle, certain immune cell subsets, and tumors. Transcriptional control involves hypoxia-inducible factors characterized by studies from the Max Planck Institute for Heart and Lung Research and the Salk Institute, while post-translational modifications such as phosphorylation and acetylation have been reported by investigators at the University of Cambridge and Harvard Medical School. Regulation has been explored in contexts ranging from athletic physiology examined by groups at the International Olympic Committee research programs to oncogenesis studied at the National Cancer Institute.
Altered activity and expression associate with cancer progression, ischemic injury, and inherited metabolic syndromes documented in clinical centers like Mayo Clinic, Cleveland Clinic, and the National Institutes of Health. Elevated isoenzyme levels correlate with poor prognosis in malignancies evaluated in cohorts from institutions such as Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center. Rare pathogenic variants have been cataloged by diagnostic consortia including ClinVar and clinical genetics units at the Children's Hospital of Philadelphia, linking enzyme deficiency to exercise intolerance and myopathy phenotypes described in case series from university hospitals in London and Toronto.
Small-molecule inhibitors and allosteric modulators have been developed by academic groups and pharmaceutical companies, with preclinical studies led by centers like Novartis research labs, teams at Pfizer, and investigators at the Dana-Farber Cancer Institute. Candidate inhibitors include substrate analogs, NAD-competitive compounds, and covalent modifiers characterized in medicinal chemistry programs at the University of California, San Francisco and Imperial College London. Clinical translation efforts intersect with trials registered through agencies such as the U.S. Food and Drug Administration and collaborative oncology consortia like European Organisation for Research and Treatment of Cancer.
The lactate dehydrogenase family exhibits paralogous genes across vertebrates, with tissue-specific isoforms studied in evolutionary laboratories at the Smithsonian Institution and the Natural History Museum, London. Comparative genomics traces divergence events using datasets from the Ensembl project and phylogenetic analyses published by research groups at the University of California, Berkeley and ETH Zurich. Functional differences among A-type and B-type subunits underpin tissue specialization described in zoological studies from museums and university departments across Europe and North America.
Biochemical assays employ spectrophotometric NADH oxidation/reduction kinetics standardized in protocols from the American Association for Clinical Chemistry and methodological papers from the Journal of Biological Chemistry. Recombinant expression, site-directed mutagenesis, and high-throughput screening have been performed using platforms available at core facilities of the European Molecular Biology Organization and national centers like the National Center for Biotechnology Information. Clinical measurement of isoenzymes uses electrophoresis and immunoassays implemented in hospital laboratories affiliated with the Royal College of Pathologists and diagnostic companies such as Roche Diagnostics.
Category:Human proteins