Hemoglobin Degradation in the Human Malaria Pathogen Plasmodium Falciparum: a Catabolic Pathway Initiated by a Specific Aspartic Protease

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 1991 Apr 1

PMID 2007860

Citations 48

Authors

D E Goldberg

A F Slater

R Beavis

B Chait

A Cerami

G B Henderson

Affiliations

Soon will be listed here.

Abstract

Hemoglobin is an important nutrient source for intraerythrocytic malaria organisms. Its catabolism occurs in an acidic digestive vacuole. Our previous studies suggested that an aspartic protease plays a key role in the degradative process. We have now isolated this enzyme and defined its role in the hemoglobinolytic pathway. Laser desorption mass spectrometry was used to analyze the proteolytic action of the purified protease. The enzyme has a remarkably stringent specificity towards native hemoglobin, making a single cleavage between alpha 33Phe and 34Leu. This scission is in the hemoglobin hinge region, unraveling the molecule and exposing other sites for proteolysis. The protease is inhibited by pepstatin and has NH2-terminal homology to mammalian aspartic proteases. Isolated digestive vacuoles make a pepstatin-inhibitable cleavage identical to that of the purified enzyme. The pivotal role of this aspartic hemoglobinase in initiating hemoglobin degradation in the malaria parasite digestive vacuoles is demonstrated.

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References

Wray W, Boulikas T, Wray V, Hancock R . Silver staining of proteins in polyacrylamide gels. Anal Biochem. 1981; 118(1):197-203. DOI: 10.1016/0003-2697(81)90179-2. View

Hempelmann E, Wilson R . Endopeptidases from Plasmodium knowlesi. Parasitology. 1980; 80(2):323-30. DOI: 10.1017/s0031182000000780. View

Fitch C, Chevli R, Banyal H, Phillips G, Pfaller M, Krogstad D . Lysis of Plasmodium falciparum by ferriprotoporphyrin IX and a chloroquine-ferriprotoporphyrin IX complex. Antimicrob Agents Chemother. 1982; 21(5):819-22. PMC: 182018. DOI: 10.1128/AAC.21.5.819. View

Vander Jagt D, Intress C, Heidrich J, Mrema J, Rieckmann K, HEIDRICH H . Marker enzymes of Plasmodium falciparum and human erythrocytes as indicators of parasite purity. J Parasitol. 1982; 68(6):1068-71. View

Aissi E, Charet P, Bouquelet S, Biguet J . Endoprotease in Plasmodium yoelii nigeriensis. Comp Biochem Physiol B. 1983; 74(3):559-66. DOI: 10.1016/0305-0491(83)90229-8. View

Sherman I, Tanigoshi L . Purification of Plasmodium lophurae cathepsin D and its effects on erythrocyte membrane proteins. Mol Biochem Parasitol. 1983; 8(3):207-26. DOI: 10.1016/0166-6851(83)90044-0. View

Krogstad D, Schlesinger P, Gluzman I . Antimalarials increase vesicle pH in Plasmodium falciparum. J Cell Biol. 1985; 101(6):2302-9. PMC: 2113995. DOI: 10.1083/jcb.101.6.2302. View

Vander Jagt D, Hunsaker L, Campos N . Characterization of a hemoglobin-degrading, low molecular weight protease from Plasmodium falciparum. Mol Biochem Parasitol. 1986; 18(3):389-400. DOI: 10.1016/0166-6851(86)90095-2. View

Fagan J, Waxman L, GOLDBERG A . Red blood cells contain a pathway for the degradation of oxidant-damaged hemoglobin that does not require ATP or ubiquitin. J Biol Chem. 1986; 261(13):5705-13. View

10.

Zarchin S, Krugliak M, Ginsburg H . Digestion of the host erythrocyte by malaria parasites is the primary target for quinoline-containing antimalarials. Biochem Pharmacol. 1986; 35(14):2435-42. DOI: 10.1016/0006-2952(86)90473-9. View

11.

Roth Jr E, Brotman D, Vanderberg J, Schulman S . Malarial pigment-dependent error in the estimation of hemoglobin content in Plasmodium falciparum-infected red cells: implications for metabolic and biochemical studies of the erythrocytic phases of malaria. Am J Trop Med Hyg. 1986; 35(5):906-11. DOI: 10.4269/ajtmh.1986.35.906. View

12.

Tang J, Wong R . Evolution in the structure and function of aspartic proteases. J Cell Biochem. 1987; 33(1):53-63. DOI: 10.1002/jcb.240330106. View

13.

Matsudaira P . Sequence from picomole quantities of proteins electroblotted onto polyvinylidene difluoride membranes. J Biol Chem. 1987; 262(21):10035-8. View

14.

Sato K, Fukabori Y, Suzuki M . Plasmodium berghei: a study of globinolytic enzyme in erythrocytic parasite. Zentralbl Bakteriol Mikrobiol Hyg A. 1987; 264(3-4):487-95. DOI: 10.1016/s0176-6724(87)80072-x. View

15.

Rosenthal P, McKerrow J, Aikawa M, Nagasawa H, LEECH J . A malarial cysteine proteinase is necessary for hemoglobin degradation by Plasmodium falciparum. J Clin Invest. 1988; 82(5):1560-6. PMC: 442723. DOI: 10.1172/JCI113766. View

16.

Weber I, Miller M, Jaskolski M, Leis J, Skalka A, Wlodawer A . Molecular modeling of the HIV-1 protease and its substrate binding site. Science. 1989; 243(4893):928-31. DOI: 10.1126/science.2537531. View

17.

Azuma T, Pals G, Mohandas T, Couvreur J, Taggart R . Human gastric cathepsin E. Predicted sequence, localization to chromosome 1, and sequence homology with other aspartic proteinases. J Biol Chem. 1989; 264(28):16748-53. View

18.

Goldberg D, Slater A, Cerami A, Henderson G . Hemoglobin degradation in the malaria parasite Plasmodium falciparum: an ordered process in a unique organelle. Proc Natl Acad Sci U S A. 1990; 87(8):2931-5. PMC: 53807. DOI: 10.1073/pnas.87.8.2931. View

19.

Beavis R, Chait B . Rapid, sensitive analysis of protein mixtures by mass spectrometry. Proc Natl Acad Sci U S A. 1990; 87(17):6873-7. PMC: 54640. DOI: 10.1073/pnas.87.17.6873. View

20.

Beavis R, Chait B . High-accuracy molecular mass determination of proteins using matrix-assisted laser desorption mass spectrometry. Anal Chem. 1990; 62(17):1836-40. DOI: 10.1021/ac00216a020. View