scholarly journals Identifying Structural Determinants of Product Specificity in Leishmania major Farnesyl Diphosphate Synthase

Biochemistry ◽  
2020 ◽  
Vol 59 (29) ◽  
pp. 2751-2759
Author(s):  
Sweta Maheshwari ◽  
Yu Seon Kim ◽  
Srinivas Aripirala ◽  
Michael Murphy ◽  
L. Mario Amzel ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Structural Determinants ◽  
Product Specificity

scholarly journals Inhibitors of Leishmania Major Farnesyl Diphosphate Synthase: Crystallographic and Calorimetric Studies

2011 ◽  
Vol 100 (3) ◽  
pp. 218a-219a
Author(s):  
Srinivas Aripirala ◽  
Sandra Gabelli ◽  
Eric Oldfield ◽  
Dolores Gonzalez Pacanowska ◽  
Mario Amzel
Keyword(s):  
Leishmania Major ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Calorimetric Studies

scholarly journals Farnesyl diphosphate synthase; regulation of product specificity.

2005 ◽  
Vol 52 (1) ◽  
pp. 45-55 ◽  
Author(s):  
Anna Szkopińska ◽  
Danuta Płochocka
Keyword(s):  
Environmental Changes ◽  
Gene Families ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Type I ◽  
Isopentenyl Diphosphate ◽  
Product Specificity ◽  
Dimethylallyl Diphosphate ◽  
Key Enzyme ◽  
Synthase Regulation

Farnesyl diphosphate synthase (FPPS) is a key enzyme in isoprenoid biosynthesis which supplies sesquiterpene precursors for several classes of essential metabolites including sterols, dolichols, ubiquinones and carotenoids as well as substrates for farnesylation and geranylgeranylation of proteins. It catalyzes the sequential head-to-tail condensation of two molecules of isopentenyl diphosphate with dimethylallyl diphosphate. The enzyme is a homodimer of subunits, typically having two aspartate-rich motifs with two sets of substrate binding sites for an allylic diphosphate and isopentenyl diphosphate per homodimer. The synthase amino-acid residues at the 4th and 5th positions before the first aspartate rich motif mainly determine product specificity. Hypothetically, type I (eukaryotic) and type II (eubacterial) FPPSs evolved from archeal geranylgeranyl diphosphate synthase by substitutions in the chain length determination region. FPPS belongs to enzymes encoded by gene families. In plants this offers the possibility of differential regulation in response to environmental changes or to herbivore or pathogen attack.

scholarly journals Farnesyl Diphosphate Synthase Is a Cytosolic Enzyme in Leishmania major Promastigotes and Its Overexpression Confers Resistance to Risedronate

2006 ◽  
Vol 5 (7) ◽  
pp. 1057-1064 ◽  
Author(s):  
Aurora Ortiz-Gómez ◽  
Carmen Jiménez ◽  
Antonio M. Estévez ◽  
Juana Carrero-Lérida ◽  
Luis M. Ruiz-Pérez ◽  
...  
Keyword(s):  
Drug Target ◽  
Leishmania Major ◽  
Intracellular Localization ◽  
Initial Step ◽  
Isoprenoid Biosynthesis ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Wild Type

ABSTRACT Farnesyl diphosphate synthase is the most likely molecular target of aminobisphosphonates (e.g., risedronate), a set of compounds that have been shown to have antiprotozoal activity both in vitro and in vivo. This protein, together with other enzymes involved in isoprenoid biosynthesis, is an attractive drug target, yet little is known about the compartmentalization of the biosynthetic pathway. Here we show the intracellular localization of the enzyme in wild-type Leishmania major promastigote cells and in transfectants overexpressing farnesyl diphosphate synthase by using purified antibodies generated towards a homogenous recombinant Leishmania major farnesyl diphosphate synthase protein. Indirect immunofluorescence, together with immunoelectron microscopy, indicated that the enzyme is mainly located in the cytoplasm of both wild-type cells and transfectants. Digitonin titration experiments also confirmed this observation. Hence, while the initial step of isoprenoid biosynthesis catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase is located in the mitochondrion, synthesis of farnesyl diphosphate by farnesyl diphosphate synthase is a cytosolic process. Leishmania major promastigote transfectants overexpressing farnesyl diphosphate synthase were highly resistant to risedronate, and the degree of resistance correlated with the increase in enzyme activity. Likewise, when resistance was induced by stepwise selection with the drug, the resulting resistant promastigotes exhibited increased levels of farnesyl diphosphate synthase. The overproduction of protein under different conditions of exposure to risedronate further supports the hypothesis that this enzyme is the main target of aminobisphosphonates in Leishmania cells.

scholarly journals Farnesyl Diphosphate Synthase Inhibitors from In Silico Screening

2013 ◽  
Vol 81 (6) ◽  
pp. 742-748 ◽  
Author(s):  
Steffen Lindert ◽  
Wei Zhu ◽  
Yi‐Liang Liu ◽  
Ran Pang ◽  
Eric Oldfield ◽  
...  
Keyword(s):  
In Silico ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
In Silico Screening
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