X-ray Structure of Malaria Peptidase Solved

The malaria parasite, Plasmodium falciparum, has limited capacity for de novo amino acid synthesis and relies on degradation of host haemoglobin for a supply of these essential building blocks. Haemoglobin is first degraded into di- and tri-peptides by the action of a number of cysteine-, aspartyl-, and metallo-proteases. These small peptide fragments are then further hydrolysed to release free amino acids by the action of the metallo-exopeptidases, PfA-M1 (an alanyl aminopeptidase) and PfA-M17 (a leucine aminopeptidase).

A team from the University of Monash has recently described the X-ray crystallographic structure of truncated recombinant PfA-M1 at a resolution of 2.1 Å. Comparison of structures of PfA-M1 bound to the known inhibitors, bestatin (K_i 500nM) and hPheP[CH₂]Phe (K_i 80nM), with the native structure showed that the enzyme did not undergo any global conformational rearrangements on binding either inhibitor. It is proposed that substrate access is achieved by means of the C-terminal domain vortex, and that control of substrate hydrolysis can be achieved, and depends on, the size of this channel. hPheP[CH₂]Phe, which provides effective protection in a murine model of malaria, also inhibits PfA-M17 and the authors suggest that inhibiting both PfA-M1 and PfA-M17 may be less likely to allow the development of drug-resistant malaria. The fact that the site of action of PfA-M1 is outside the digestive vacuole, together with the comparative ease of identifying drug-like inhibitors of metallo-proteases, makes PfA-M1 an attractive target for new anti-malarial therapies.

The study is published in the February 5^th Early Edition of PNAS.