TY - JOUR
T1 - Host biotin is required for liver stage development in malaria parasites
AU - Dellibovi-Ragheb, Teegan A.
AU - Jhun, Hugo
AU - Goodman, Christopher D.
AU - Walters, Maroya S.
AU - Ragheb, Daniel R.T.
AU - Matthews, Krista A.
AU - Rajaram, Krithika
AU - Mishra, Satish
AU - McFadden, Geoffrey I.
AU - Sinnis, Photini
AU - Prigge, Sean T.
N1 - Funding Information:
We are grateful to Dr. Stuart A. Ralph and Dr. Lee Yeoh for assistance with splice variant analysis; the MR4 for providing us with malaria parasites contributed by A. P. Waters and other reagents; Dr. Stefan Kappe and Nelly Camargo for providing us with UIS4 protein for antisera generation; Dr. David Fidock for the ΔFabI parasite line; Dr. Paul Watkins for radiolabeled standards; Dr. Diego Espinosa, Dr. Christine Hopp, and Dr. Yevel Garcia for technical assistance; and Christopher Kizito and the Malaria Research Institute insect core facilities for providing mosquitoes. This work was supported by the National Institutes of Health (NIH) Grants R01 AI065853 (to S.T.P.), R01 AI125534 (to S.T.P.), and R01 AI056840 (to P.S.); NIH National Center for Research Resources Grant UL1 RR025005; the Johns Hopkins Malaria Research Institute; the Bloomberg Family Foundation; and a Program Grant from the Australian National Health and Medical Research Council.
Funding Information:
with malaria parasites contributed by A. P. Waters and other reagents; Dr. Stefan Kappe and Nelly Camargo for providing us with UIS4 protein for antisera generation; Dr. David Fidock for the ΔFabI parasite line; Dr. Paul Wat-kins for radiolabeled standards; Dr. Diego Espinosa, Dr. Christine Hopp, and Dr. Yevel Garcia for technical assistance; and Christopher Kizito and the Malaria Research Institute insect core facilities for providing mosquitoes. This work was supported by the National Institutes of Health (NIH) Grants R01 AI065853 (to S.T.P.), R01 AI125534 (to S.T.P.), and R01 AI056840 (to P.S.); NIH National Center for Research Resources Grant UL1 RR025005; the Johns Hopkins Malaria Research Institute; the Bloomberg Family Foundation; and a Program Grant from the Australian National Health and Medical Research Council.
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018
Y1 - 2018
N2 - Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that is the target of several classes of herbicides. Malaria parasites contain a plant-like ACC, and this is the only protein predicted to be biotinylated in the parasite. We found that ACC is expressed in the apicoplast organelle in liver- and blood-stage malaria parasites; however, it is activated through biotinylation only in the liver stages. Consistent with this observation, deletion of the biotin ligase responsible for ACC biotinylation does not impede blood-stage growth, but results in late liver-stage developmental defects. Biotin depletion increases the severity of the developmental defects, demonstrating that parasite and host biotin metabolism are required for normal liver-stage progression. This finding may link the development of liver-stage malaria parasites to the nutritional status of the host, as neither the parasite nor the human host can synthesize biotin.
AB - Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that is the target of several classes of herbicides. Malaria parasites contain a plant-like ACC, and this is the only protein predicted to be biotinylated in the parasite. We found that ACC is expressed in the apicoplast organelle in liver- and blood-stage malaria parasites; however, it is activated through biotinylation only in the liver stages. Consistent with this observation, deletion of the biotin ligase responsible for ACC biotinylation does not impede blood-stage growth, but results in late liver-stage developmental defects. Biotin depletion increases the severity of the developmental defects, demonstrating that parasite and host biotin metabolism are required for normal liver-stage progression. This finding may link the development of liver-stage malaria parasites to the nutritional status of the host, as neither the parasite nor the human host can synthesize biotin.
KW - Acetyl-CoA carboxylase
KW - Apicoplast
KW - Biotin ligase
KW - Holocarboxylase synthetase
KW - Plasmodium
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UR - http://www.scopus.com/inward/citedby.url?scp=85043772886&partnerID=8YFLogxK
U2 - 10.1073/pnas.1800717115
DO - 10.1073/pnas.1800717115
M3 - Article
C2 - 29483266
AN - SCOPUS:85043772886
SN - 0027-8424
VL - 115
SP - E2604-E2613
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -