Linked Life Data

8679569

Source:http://linkedlifedata.com/resource/pubmed/id/8679569

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
25
pubmed:dateCreated
1996-8-20
pubmed:abstractText
Ras proteins are mutationally activated in a variety of human cancers. Since farnesylation of Ras proteins is required for expression of their oncogenic potential, the enzyme responsible for this reaction, farnesyl:protein transferase (FPT), has become a major target for anticancer drug development. FPT is a zinc metalloenzyme, and the zinc is essential for its catalytic activity. To begin to elucidate the role of zinc in catalysis, we initiated metal substitution studies. Of all metals tested, only cadmium was able to functionally substitute for zinc, reconstituting enzymatic activity with native substrates (H-Ras and farnesyl diphosphate) to about 50% of that of the zinc-containing enzyme. Several important differences were observed between cadmium-substituted FPT (Cd-FPT) and zinc-containing FPT (Zn-FPT). Cd-FPT not only uses H-ras with its native CaaX motif (Ras-CVLS) as a substrate but also can farnesylate H-ras in which the CaaX motif is altered to contain a C-terminal leucine residue (Ras-CVLL). Similarly, Cd-FPT can farnesylate leucine-terminated peptides. Leucine-terminated proteins and peptides are usually substrates for the related enzyme geranylgeranyl:protein transferase type I. Farnesylation of Ras-CVLS and Ras-CVLL by Cd-FPT exhibited similar sensitivity to the FPT inhibitor SCH 44342 and to the peptide inhibitor CAIM. However, unlike Zn-FPT, Cd-FPT is also potently inhibited by the leucine-terminated peptide CAIL. These results indicate that the metal ion content of FPT strongly influences its protein substrate specificity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8166-71
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
Substitution of cadmium for zinc in farnesyl:protein transferase alters its substrate specificity.
pubmed:affiliation
Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033 USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't