hemoglobin cleavage site-specificity of the plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3血红蛋白位点特异性使之乳沟恶性疟原虫的半胱氨酸蛋白酶falcipain-2 falcipain-3.pdfVIP

Hemoglobin Cleavage Site-Specificity of the Plasmodium falciparum Cysteine Proteases Falcipain-2 and Falcipain-3 1¤a 2¤b 3¤c 2 2 Shoba Subramanian , Markus Hardt , Youngchool Choe , Richard K. Niles , Eric B. Johansen , 1 1 4 3 1 Jennifer Legac , Jiri Gut , Iain D. Kerr , Charles S. Craik , Philip J. Rosenthal * 1 Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, California, United States of America, 2 Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, California, United States of America, 3 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America, 4 Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America Abstract The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 degrade host hemoglobin to provide free amino acids for parasite protein synthesis. Hemoglobin hydrolysis has been described as an ordered process initiated by aspartic proteases, but cysteine protease inhibitors completely block the process, suggesting that cysteine proteases can also initiate hemoglobin hydrolysis. To characterize the specific roles of falcipains, we used three approaches. First, using random P1 – P4 amino acid substrate libraries, falcipain-2 and falcipain-3 demonstrated strong preference for cleavage sites with Leu at the P2 position. Second, with overlapping peptides spanning a and b globin and proteo