STRUCTURE, REGULATION AND EVOLUTION OF VERTEBRATE LACTATE-DEHYDROGENASE GENES

In vertebrates, L-lactate dehydrogenase (LDH) isozymes A (muscle) and B (heart) are best suited for pyruvate reduction and lactate oxidation , respectively. In mammals and columbid birds, a 3rd LDH-C isozyme is expressed in testis. In advanced teleost fish a 3rd LDH isozyme is fou nd only in the eye, but in more primitive teleosts, ii it is present, it has a generalized distribution. The evolutionary relationships amon g these 3rd forms of LDH isozymes have not been completely resolved. W e have cloned the cDNAs encoding LDH-A, LDH-B, and/or LDH-C isozymes f rom the human, mouse, rat, porcine, pigeon, alligator, lizard, turtle, Xenopus, and a nematode. We have determined the exon-intron organizat ion of human LDH-A, LDH-B, and LDH-C genes, and the complete sequence of 12 851 nucleotides of the mouse LDH-A gene. The protein-coding sequ ences of the mammalian LDH-A, LDH-B, and LDH-C genes, as well as duck LDH-B gene, are interrupted by 6 introns at homologous positions. The expression of vertebrate LDH-A, LDH-B, and LDH-C genes is tissue speci fic and developmentally regulated. Expression of the mammalian LDH-A g ene was also shown to be induced by cAMP and estrogen. In collaboratio n with Dr. Wen-Hsiung Li, we analyzed the evolutionary relationships a mong vertebrate LDH isoyzmes. Contrary to the common opinion that the turtle lineage branched off before the divergence between the lizard/a lligator and bird lineages, the turtle lineage was found clustered wit h either the alligator lineage or the alligator-bird clade, while the lizard lineage was found to have branched off before the divergence be tween the alligator/turtle and bird lineages. The pigeon testicular LD H-C gene was evidently duplicated from the LDH-B (heart) gene, so it i s not orthologous to the mammalian testicular LDH-C genes, which appea r to be derived from the LDH-A (muscle) gene.