Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis

Misty L. Kuhn; Evan Alexander; George Minasov; Holland J. Page; Zdzislaw Warwrzak; Ludmilla Shuvalova; Kristin J. Flores; Daniel J. Wilson; Ce Shi; Courtney C. Aldrich; Wayne F. Anderson

doi:10.1021/acsinfecdis.6b00082

Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis

Misty L. Kuhn, Evan Alexander, George Minasov, Holland J. Page, Zdzislaw Warwrzak, Ludmilla Shuvalova, Kristin J. Flores, Daniel J. Wilson, Ce Shi, Courtney C. Aldrich^*, Wayne F. Anderson

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Mycolic acids are indispensible lipids of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. FadD32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (FAS) and polyketide synthase (PKS) biosynthetic pathways. FadD32, a fatty acyl-AMP ligase (FAAL), represents one of the best genetically and chemically validated new TB drug targets. We have determined the three-dimensional crystal structure of Mtb FadD32 in complex with a ligand specifically designed to stabilize the catalytically active adenylate-conformation, which provides a foundation for structure-based drug design efforts against this essential protein. The structure also captures the unique interactions of a FAAL-specific insertion sequence and provides insight into the specificity and mechanism of fatty acid transfer.

Original language	English (US)
Pages (from-to)	579-591
Number of pages	13
Journal	ACS Infectious Diseases
Volume	2
Issue number	8
DOIs	https://doi.org/10.1021/acsinfecdis.6b00082
State	Published - Aug 12 2016

Funding

This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health a n d Human S e r v i c e s , u n d e r c o n t r a c t n o s . HHSN272200700058C and HHSN272201200026C (to W.F.A.). C.C.A. acknowledges support from the NIH (1- U54-AI-057153, AI070291). Some support was also provided as a subgrantee of the SGC under a Bill and Melinda Gates Foundation grant for the Structure-Guided Drug Discovery Coalition (SDDC). Additional funding for this project includes San Francisco State University Startup funds (to M.L.K.). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817).

Keywords

FadD32
Mycobacterium tuberculosis
fatty acyl-AMP ligase
mycolic acid biosynthesis

ASJC Scopus subject areas

Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acsinfecdis.6b00082

Cite this

@article{10858f733cfc4c9397c63731c0c003d0,

title = "Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis",

abstract = "Mycolic acids are indispensible lipids of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. FadD32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (FAS) and polyketide synthase (PKS) biosynthetic pathways. FadD32, a fatty acyl-AMP ligase (FAAL), represents one of the best genetically and chemically validated new TB drug targets. We have determined the three-dimensional crystal structure of Mtb FadD32 in complex with a ligand specifically designed to stabilize the catalytically active adenylate-conformation, which provides a foundation for structure-based drug design efforts against this essential protein. The structure also captures the unique interactions of a FAAL-specific insertion sequence and provides insight into the specificity and mechanism of fatty acid transfer.",

keywords = "FadD32, Mycobacterium tuberculosis, fatty acyl-AMP ligase, mycolic acid biosynthesis",

author = "Kuhn, {Misty L.} and Evan Alexander and George Minasov and Page, {Holland J.} and Zdzislaw Warwrzak and Ludmilla Shuvalova and Flores, {Kristin J.} and Wilson, {Daniel J.} and Ce Shi and Aldrich, {Courtney C.} and Anderson, {Wayne F.}",

note = "Funding Information: This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health a n d Human S e r v i c e s , u n d e r c o n t r a c t n o s . HHSN272200700058C and HHSN272201200026C (to W.F.A.). C.C.A. acknowledges support from the NIH (1- U54-AI-057153, AI070291). Some support was also provided as a subgrantee of the SGC under a Bill and Melinda Gates Foundation grant for the Structure-Guided Drug Discovery Coalition (SDDC). Additional funding for this project includes San Francisco State University Startup funds (to M.L.K.). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817). Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = aug,

day = "12",

doi = "10.1021/acsinfecdis.6b00082",

language = "English (US)",

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T1 - Structure of the Essential Mtb FadD32 Enzyme

T2 - A Promising Drug Target for Treating Tuberculosis

AU - Kuhn, Misty L.

AU - Alexander, Evan

AU - Minasov, George

AU - Page, Holland J.

AU - Warwrzak, Zdzislaw

AU - Shuvalova, Ludmilla

AU - Flores, Kristin J.

AU - Wilson, Daniel J.

AU - Shi, Ce

AU - Aldrich, Courtney C.

AU - Anderson, Wayne F.

N1 - Funding Information: This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health a n d Human S e r v i c e s , u n d e r c o n t r a c t n o s . HHSN272200700058C and HHSN272201200026C (to W.F.A.). C.C.A. acknowledges support from the NIH (1- U54-AI-057153, AI070291). Some support was also provided as a subgrantee of the SGC under a Bill and Melinda Gates Foundation grant for the Structure-Guided Drug Discovery Coalition (SDDC). Additional funding for this project includes San Francisco State University Startup funds (to M.L.K.). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817). Publisher Copyright: © 2016 American Chemical Society.

PY - 2016/8/12

Y1 - 2016/8/12

N2 - Mycolic acids are indispensible lipids of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. FadD32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (FAS) and polyketide synthase (PKS) biosynthetic pathways. FadD32, a fatty acyl-AMP ligase (FAAL), represents one of the best genetically and chemically validated new TB drug targets. We have determined the three-dimensional crystal structure of Mtb FadD32 in complex with a ligand specifically designed to stabilize the catalytically active adenylate-conformation, which provides a foundation for structure-based drug design efforts against this essential protein. The structure also captures the unique interactions of a FAAL-specific insertion sequence and provides insight into the specificity and mechanism of fatty acid transfer.

AB - Mycolic acids are indispensible lipids of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. FadD32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (FAS) and polyketide synthase (PKS) biosynthetic pathways. FadD32, a fatty acyl-AMP ligase (FAAL), represents one of the best genetically and chemically validated new TB drug targets. We have determined the three-dimensional crystal structure of Mtb FadD32 in complex with a ligand specifically designed to stabilize the catalytically active adenylate-conformation, which provides a foundation for structure-based drug design efforts against this essential protein. The structure also captures the unique interactions of a FAAL-specific insertion sequence and provides insight into the specificity and mechanism of fatty acid transfer.

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KW - mycolic acid biosynthesis

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Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

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2.25 Angstrom Resolution Crystal Structure of Long-chain-fatty-acid-AMP Ligase FadD32 from Mycobacterium tuberculosis in complex with Inhibitor 5'-O-[(11-phenoxyundecanoyl)sulfamoyl]adenosine

Cite this

Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Datasets

2.25 Angstrom Resolution Crystal Structure of Long-chain-fatty-acid-AMP Ligase FadD32 from Mycobacterium tuberculosis in complex with Inhibitor 5'-O-[(11-phenoxyundecanoyl)sulfamoyl]adenosine

Cite this