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Development of chemical proteomics for the folateome and analysis of the kinetoplastid folateome

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Development of chemical proteomics for the folateome and analysis of the kinetoplastid folateome. / Webster, Lauren A.; Thomas, Michael; Urbaniak, Michael Daniel; Wyllie, Susan; Ong, Han B.; Tinti, Michele; Fairlamb, Alan H.; Boesche, Markus; Ghidelli-Disse, Sonja; Drewes, Gerard; Gilbert, Ian H.

In: ACS Infectious Diseases, Vol. 4, No. 10, 12.10.2018, p. 1475-1486.

Research output: Contribution to journalJournal article

Harvard

Webster, LA, Thomas, M, Urbaniak, MD, Wyllie, S, Ong, HB, Tinti, M, Fairlamb, AH, Boesche, M, Ghidelli-Disse, S, Drewes, G & Gilbert, IH 2018, 'Development of chemical proteomics for the folateome and analysis of the kinetoplastid folateome' ACS Infectious Diseases, vol. 4, no. 10, pp. 1475-1486. https://doi.org/10.1021/acsinfecdis.8b00097

APA

Webster, L. A., Thomas, M., Urbaniak, M. D., Wyllie, S., Ong, H. B., Tinti, M., ... Gilbert, I. H. (2018). Development of chemical proteomics for the folateome and analysis of the kinetoplastid folateome. ACS Infectious Diseases, 4(10), 1475-1486. https://doi.org/10.1021/acsinfecdis.8b00097

Vancouver

Webster LA, Thomas M, Urbaniak MD, Wyllie S, Ong HB, Tinti M et al. Development of chemical proteomics for the folateome and analysis of the kinetoplastid folateome. ACS Infectious Diseases. 2018 Oct 12;4(10):1475-1486. https://doi.org/10.1021/acsinfecdis.8b00097

Author

Webster, Lauren A. ; Thomas, Michael ; Urbaniak, Michael Daniel ; Wyllie, Susan ; Ong, Han B. ; Tinti, Michele ; Fairlamb, Alan H. ; Boesche, Markus ; Ghidelli-Disse, Sonja ; Drewes, Gerard ; Gilbert, Ian H. / Development of chemical proteomics for the folateome and analysis of the kinetoplastid folateome. In: ACS Infectious Diseases. 2018 ; Vol. 4, No. 10. pp. 1475-1486.

Bibtex

@article{b4d92781ed1f4bcc96a5161c06663251,
title = "Development of chemical proteomics for the folateome and analysis of the kinetoplastid folateome",
abstract = "The folate pathway has been extensively studied in a number of organisms, with its essentiality exploited by a number of drugs. However, there has been little success in developing drugs that target folate metabolism in the kinetoplastids. Despite compounds being identified which show significant inhibition of the parasite enzymes, this activity does not translate well into cellular and animal models of disease. Understanding to which enzymes antifolates bind under physiological conditions and how this corresponds to the phenotypic response could provide insight on how to target the folate pathway in these organisms. To facilitate this, we have adopted a chemical proteomics approach to study binding of compounds to enzymes of folate metabolism. Clinical and literature antifolate compounds were immobilized onto resins to allow for “pull down” of the proteins in the “folateome”. Using competition studies, proteins, which bind the beads specifically and nonspecifically, were identified in parasite lysate (Trypanosoma brucei and Leishmania major) for each antifolate compound. Proteins were identified through tryptic digest, tandem mass tag (TMT) labeling of peptides followed by LC-MS/MS. This approach was further exploited by creating a combined folate resin (folate beads). The resin could pull down up to 9 proteins from the folateome. This information could be exploited in gaining a better understanding of folate metabolism in kinetoplastids and other organisms.",
keywords = "chemical proteomics, folate, kinetoplastid, Leishmania, pull down, Trypanosoma brucei",
author = "Webster, {Lauren A.} and Michael Thomas and Urbaniak, {Michael Daniel} and Susan Wyllie and Ong, {Han B.} and Michele Tinti and Fairlamb, {Alan H.} and Markus Boesche and Sonja Ghidelli-Disse and Gerard Drewes and Gilbert, {Ian H.}",
year = "2018",
month = "10",
day = "12",
doi = "10.1021/acsinfecdis.8b00097",
language = "English",
volume = "4",
pages = "1475--1486",
journal = "ACS Infectious Diseases",
publisher = "American Chemical Society",
number = "10",

}

RIS

TY - JOUR

T1 - Development of chemical proteomics for the folateome and analysis of the kinetoplastid folateome

AU - Webster, Lauren A.

AU - Thomas, Michael

AU - Urbaniak, Michael Daniel

AU - Wyllie, Susan

AU - Ong, Han B.

AU - Tinti, Michele

AU - Fairlamb, Alan H.

AU - Boesche, Markus

AU - Ghidelli-Disse, Sonja

AU - Drewes, Gerard

AU - Gilbert, Ian H.

PY - 2018/10/12

Y1 - 2018/10/12

N2 - The folate pathway has been extensively studied in a number of organisms, with its essentiality exploited by a number of drugs. However, there has been little success in developing drugs that target folate metabolism in the kinetoplastids. Despite compounds being identified which show significant inhibition of the parasite enzymes, this activity does not translate well into cellular and animal models of disease. Understanding to which enzymes antifolates bind under physiological conditions and how this corresponds to the phenotypic response could provide insight on how to target the folate pathway in these organisms. To facilitate this, we have adopted a chemical proteomics approach to study binding of compounds to enzymes of folate metabolism. Clinical and literature antifolate compounds were immobilized onto resins to allow for “pull down” of the proteins in the “folateome”. Using competition studies, proteins, which bind the beads specifically and nonspecifically, were identified in parasite lysate (Trypanosoma brucei and Leishmania major) for each antifolate compound. Proteins were identified through tryptic digest, tandem mass tag (TMT) labeling of peptides followed by LC-MS/MS. This approach was further exploited by creating a combined folate resin (folate beads). The resin could pull down up to 9 proteins from the folateome. This information could be exploited in gaining a better understanding of folate metabolism in kinetoplastids and other organisms.

AB - The folate pathway has been extensively studied in a number of organisms, with its essentiality exploited by a number of drugs. However, there has been little success in developing drugs that target folate metabolism in the kinetoplastids. Despite compounds being identified which show significant inhibition of the parasite enzymes, this activity does not translate well into cellular and animal models of disease. Understanding to which enzymes antifolates bind under physiological conditions and how this corresponds to the phenotypic response could provide insight on how to target the folate pathway in these organisms. To facilitate this, we have adopted a chemical proteomics approach to study binding of compounds to enzymes of folate metabolism. Clinical and literature antifolate compounds were immobilized onto resins to allow for “pull down” of the proteins in the “folateome”. Using competition studies, proteins, which bind the beads specifically and nonspecifically, were identified in parasite lysate (Trypanosoma brucei and Leishmania major) for each antifolate compound. Proteins were identified through tryptic digest, tandem mass tag (TMT) labeling of peptides followed by LC-MS/MS. This approach was further exploited by creating a combined folate resin (folate beads). The resin could pull down up to 9 proteins from the folateome. This information could be exploited in gaining a better understanding of folate metabolism in kinetoplastids and other organisms.

KW - chemical proteomics

KW - folate

KW - kinetoplastid

KW - Leishmania

KW - pull down

KW - Trypanosoma brucei

U2 - 10.1021/acsinfecdis.8b00097

DO - 10.1021/acsinfecdis.8b00097

M3 - Journal article

VL - 4

SP - 1475

EP - 1486

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 10

ER -