Mechanistic Studies of Lipoic Acid Synthase

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Lipoic acid is an essential
sulfur-containing cofactor of several multienzyme complexes that are involved
in primary metabolism. It has been known for a number of years to be derived
directly from octanoic acid, but the mechanism of sulfur insertion into the
unactivated fatty acid has remained obscure. Recently, a gene has been cloned
which appears to be the catalytic core of the enzymatic activity that is
involved in the sulfur insertion reaction. Signature motifs within its deduced
primary sequence and initial spectroscopic characterization of the protein
collectively indicate that this "lipoic acid synthase" belongs to an emerging
class of enzymes that contain iron-sulfur clusters, and that use
S-adenosyl-L-methionine as a means of generating carbon-centered radical
intermediates in enzymatic reactions. The roles of S-adenosyl-L-methionine and
iron-sulfur clusters in this class of enzymes represent departures from the
roles that they have traditionally been assigned in biochemical textbooks.
Iron-sulfur clusters have traditionally been thought of as electron transfer
agents or Lewis acid catalysts, while S-adenosyl-L-methionine is still
considered to be mainly a cellular methylating agent. The experiments proposed
herein seek to reveal the "new" molecular enzymology associated with these
cofactors. Several experimental mechanisms are discussed, and experiments are
proposed that will distinguish among them.

Aside from the involvement of lipoic acid as a cofactor in enzyme complexes of
energy metabolism, it is known to modulate glucose metabolism in patients with
type II diabetes and to serve as a general cellular antioxidant, among many
other things. There is significant evidence that lipoic acid can be
endogenously synthesized in mammalian cells. Experiments outlined in this
proposal will lay a foundation upon which studies to address whether the
inability to synthesize lipoic acid endogenously can lead to a compromising of
cellular function.
StatusFinished
Effective start/end date4/1/022/28/12

Funding

  • National Institute of General Medical Sciences: $251,980.00
  • National Institute of General Medical Sciences: $230,499.00
  • National Institute of General Medical Sciences: $224,299.00
  • National Institute of General Medical Sciences: $230,110.00
  • National Institute of General Medical Sciences: $230,308.00
  • National Institute of General Medical Sciences: $91,041.00
  • National Institute of General Medical Sciences: $252,498.00
  • National Institute of General Medical Sciences: $252,243.00
  • National Institute of General Medical Sciences: $229,907.00
  • National Institute of General Medical Sciences: $249,192.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.