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Exp Parasitol. 1997 Jan;85(1):63-76.

Leishmania major: comparison of the cathepsin L- and B-like cysteine protease genes with those of other trypanosomatids.

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Department of Pathology, University of California, V. A. Medical Center, San Francisco 94121, USA.


Cysteine proteases play important roles in the pathogenesis of several parasitic infections and have been proposed as targets for the structure-based strategy of drug design. As a first step toward applying this strategy to design inhibitors as antiparasitic agents for leishmaniasis, we have isolated and sequenced the full-length clones of two cysteine protease genes from Leishmania major. One of the genes is structurally similar to the cathepsin L-like family and the other is similar to the cathepsin B-like family of cysteine proteases. The L. major cathepsin L-like sequence has a proregion that shares high sequence similarity with other cathepsin L sequences but not cathepsin B sequences and has a proline/threonine-rich C-terminal extension. The cathepsin L-like gene occurs in multiple copies, whereas there may be only one copy of the cathepsin B-like gene. Northern blot analyses show that both genes are expressed in the promastigote and amastigote stages, and pulse field gel electrophoresis revealed that the cathepsin L- and B-like genes are each found on two nonhomologous chromosomes. The L. major L-like amino acid sequence is 75% identical to the L. mexicana sequence, 74% identical to the L. pifanoi sequence, 47% identical with the Trypanosoma cruzi sequence, 47% identical with the T. congolense sequence, and 45% identical with the T. brucei sequence. L. major is one of two trypanosomatid species for which a cathepsin B-like gene has been identified and sequenced; its amino acid sequence is 82% identical to the one from L. mexicana. Tree inference based on distance and parsimony methods of kinetoplastid cathepsin L proteins yielded independent support for phylogenetic hypotheses inferred from analyses of ribosomal RNA genes. Because the cathepsin L locus has a high level of phylogenetic signal with respect to trypanosomatid taxa, this locus has great potential utility for investigating the evolutionary history of trypanosomatids and related organisms.

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