Farnesyl transferase

Protein farnesyltransferase
Identifiers
EC number CAS number IntEnz BRENDA ExPASy KEGG MetaCyc metabolic pathway
PRIAM PDB structures PDBsum
Gene Ontology EGO

Farnesyltransferase (cancers.

Farnesyltransferase catalyzes the chemical reaction

farnesyl diphosphate + protein-cysteine \rightleftharpoons S-farnesyl protein + diphosphate

Thus, the two substrates of this enzyme are farnesyl diphosphate and protein-cysteine, whereas its two products are S-farnesyl protein and diphosphate.

Overview

Farnesyltransferase posttranslationally-modifies proteins by adding an isoprenoid lipid called a farnesyl group to the -SH of the cysteine near the end of target proteins to form a thioether linkage. This process, called farnesylation (which is a type of prenylation), causes farnesylated proteins to become membrane-associated due to the hydrophobic nature of the farnesyl group. Most farnesylated proteins are involved in cellular signaling wherein membrane association is critical for function.

Farnesyltransferase structure and function

Farnesyltransferase has two subunits: a 48kDa alpha subunit and a 46kDa beta subunit. Both subunits are primarily composed of alpha helices. The α subunit is made of a double layer of paired alpha helices stacked in parallel, which wraps partly around the beta subunit like a blanket. The alpha helices of the β subunit form a barrel. The active site is formed by the center of the β subunit flanked by part of the α subunit. Farnesyltransferase coordinates a zinc cation on its β subunit at the lip of the active site. Farnesyltransferase has a hydrophobic binding pocket for farnesyl diphosphate, the lipid donor molecule. All farnesyltransferase substrates have a cysteine as their fourth-to-last residue. This cysteine engages in an SN2 type attack, coordinated by the zinc and a transient stabilizing magnesium ion on the farnesyl diphosphate, displacing the diphosphate. The product remains bound to farnesyltransferase until displaced by new substrates. The last three amino acids of the CaaX motif are removed later.

Specificity

There are four binding pockets in FTase, which accommodate the last four amino acids on the carboxyl-terminus of a protein. Only those with a suitable CaaX motif can bind ('C' is Cysteine, 'a' is an aliphatic amino acid, and 'X' is variable). The carboxyl-terminal amino acid (X) discriminates FTase’s targets from those of the other prenyltransferases, allowing only six different amino acids to bind with any affinity. It has been shown that geranylgeranyltransferase can prenylate some of the substrates of Farnesyltransferase and vice versa.

Structural studies

As of late 2007, 15 2IEJ.

References

  • Sinnott, M. (Ed.), Comprehensive Biological Catalysis. A Mechanistic Reference, vol. 1, Academic Press, San Diego, CA, 1998, p. 31-118.

See also

External links

  • EurekAlert: NIH, UNC scientists find anti-cancer drugs might work in treating deadly aging disease
  • Medical Subject Headings (MeSH)
  • 2.5.1.29
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