-
Structure — LDHA (M-type)
Human muscle L-lactate dehydrogenase M chain, ternary complex with NADH and oxamate 1I10 (Read JA, Winter VJ, Eszes CM, Sessions RB & Brady RL, Protein Sci 2001, PMID:11352716).
-
LDHA & cancer — why cancers love this enzyme
Most cancer cells rely on aerobic glycolysis (the Warburg effect) rather than oxidative phosphorylation to fuel proliferation; this drives glucose uptake and pyruvate → lactate flux, exactly the LDHA reaction — Vander Heiden MG, Cantley LC & Thompson CB, Science 2009, PMID:19460998. Hypoxia-inducible factor 1 (HIF-1) binds hypoxia response elements in the LDHA promoter and transcriptionally upregulates it, so hypoxic tumors boost LDHA — Semenza GL et al., J Biol Chem 1996, PMID:8955077. Knocking down LDH-A in tumor cells impairs their proliferation under hypoxia and diminishes tumorigenicity, making LDHA a proposed anti-cancer target — Fantin VR, St-Pierre J & Leder P, Cancer Cell 2006, PMID:16766262. (Total serum LDH is a classical, routinely used prognostic/biomarker in clinical oncology — elevated in many advanced solid tumors.)
-
Structure — LDHB (H-type)
Human heart L-lactate dehydrogenase H chain, ternary complex with NADH and oxamate 1I0Z (same authors, same paper, PMID:11352716). The two folds are essentially indistinguishable (~83% identical; same domain structure, subunit association, and active-site architecture). On the LDHB tab the viewer now displays the real 1I0Z H-chain backbone and its own catalytic residues (His193, Arg105, Arg168, Asp167, Thr247, superposed onto the shared frame, Cα RMSD ≈ 0.8 Å), whereas the Overview/LDHA tabs keep the 1I10 M-chain structure. The physiological difference remains kinetic, not structural: it shows up in which substrate is favored to bind and which direction the reaction runs, not in a different fold. The viewer therefore signals the isoform by the backbone, the docking substrate and the reaction direction (LDHA → lactate · LDHB → pyruvate).
-
① NADH binds
NADH docks with nicotinamide ring positioned near His193; the hydride donor atom (C4N) faces the substrate binding site. NADH coordinates from 1I10 (NAI ligand).
-
② Substrate differs by isoform
The initial substrate is not the same per isoform. LDHA binds pyruvate (a keto acid, C=O at C2) and reduces it to lactate; LDHB binds L-lactate (a hydroxy acid, C–OH at C2) and oxidizes it back to pyruvate. In the viewer, the LDHA tab shows the pyruvate-analog oxamate docking, while the LDHB tab shows a schematic L-lactate with its C2 hydroxyl facing the nicotinamide ring. Substrate pose anchored from oxamate in 1I10 (OXM ligand).
-
③ Hydride transfer + proton relay
[schematic] His193 donates/accepts a proton to the substrate carbonyl carbon; simultaneously, the nicotinamide C4 transfers a hydride to the same carbon. In LDHA: NADH→NAD⁺ + pyruvate→lactate. In LDHB: the reverse (lactate→pyruvate + NAD⁺→NADH). The mobile loop (residues 96–107, Arg105) closes to shield the active site.
-
④ Products released
LDHA: lactate + NAD⁺ released. LDHB: pyruvate + NADH released. The reaction is freely reversible; the direction is determined by substrate concentrations and kinetic properties of each isoform.
-
Isozymes — why names differ
LDHA (gene LDHA, chromosome 11p15) encodes the M (muscle) subunit; LDHB (gene LDHB, chromosome 12p12) encodes the H (heart) subunit. These are paralogous genes (gene duplication; ~83% amino acid identity). The critical kinetic difference: a single Ala→Gln substitution in the active-site loop makes LDHB strongly inhibited by excess pyruvate (aerobic tissues favor lactate→pyruvate), while LDHA resists pyruvate inhibition (anaerobic tissues favor pyruvate→lactate). Five tetrameric isozymes (LDH-1 H₄ through LDH-5 M₄) reflect the tissue-specific ratio of M and H subunits.
-
Sequence
LDHA: DNA/gene NCBI Gene 3939 · protein UniProt P00338 · LDHB: DNA/gene NCBI Gene 3945 · protein UniProt P07195
› Backbones and ligand poses are taken directly from the listed PDB entries,
superposed into one common frame. Where no crystalline state exists for a step
(e.g., Michaelis geometry), the pose is drawn schematically using PubChem 3D
geometries and is labeled as such in the narration.