Probing Enzymes Late in the Trypanosomal Glycosylphosphatidylinositol Biosynthetic Pathway with Synthetic Glycosylphosphatidylinositol Analogues

TY - JOUR

T1 - Probing Enzymes Late in the Trypanosomal Glycosylphosphatidylinositol Biosynthetic Pathway with Synthetic Glycosylphosphatidylinositol Analogues

AU - Urbaniak, Michael D.

AU - Yashunsky, Dmitry V.

AU - Crossman, Arthur

AU - Nikolaev, Andrei V.

AU - Ferguson, Michael A. J.

PY - 2008/10

Y1 - 2008/10

N2 - Glycosylphosphatidylinositol (GPI)-anchored proteins are abundant in the protozoan parasite Tryponosoma brucei, the causative agent of African sleeping sickness in humans and the related disease Nagana in cattle, and disruption of GPI biosynthesis is genetically and chemically validated as a drug target. Here, we examine the ability of enzymes of the trypanosomal GPI biosynthetic pathway to recognize and process a series of synthetic dimannosyl-glucos-aminylphosphatidylinositol analogues containing systematic modifications on the mannose residues. The data reveal which portions of the natural substrate are important for recognition, explain why mannosylation occurs prior to inositol acylation in the trypanosomal pathway, and identify the first inhibitor of the third alpha-mannosyltransferase of the GPI biosynthetic pathway.

AB - Glycosylphosphatidylinositol (GPI)-anchored proteins are abundant in the protozoan parasite Tryponosoma brucei, the causative agent of African sleeping sickness in humans and the related disease Nagana in cattle, and disruption of GPI biosynthesis is genetically and chemically validated as a drug target. Here, we examine the ability of enzymes of the trypanosomal GPI biosynthetic pathway to recognize and process a series of synthetic dimannosyl-glucos-aminylphosphatidylinositol analogues containing systematic modifications on the mannose residues. The data reveal which portions of the natural substrate are important for recognition, explain why mannosylation occurs prior to inositol acylation in the trypanosomal pathway, and identify the first inhibitor of the third alpha-mannosyltransferase of the GPI biosynthetic pathway.

KW - AFRICAN SLEEPING SICKNESS

KW - DE-N-ACETYLASE

KW - PHOSPHATIDYLINOSITOL MEMBRANE ANCHORS

KW - VARIANT SURFACE GLYCOPROTEIN

KW - GPI BIOSYNTHESIS

KW - INOSITOL-ACYLATION

KW - SUBSTRATE-SPECIFICITY

KW - TRANSFERRIN RECEPTOR

KW - BRUCEI

KW - INHIBITION

UR - https://www.scopus.com/pages/publications/58149164667

U2 - 10.1021/cb800143w

DO - 10.1021/cb800143w

M3 - Article

C2 - 18928250

SN - 1554-8929

VL - 3

SP - 625

EP - 634

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 10

ER -