Branched-Chain Amino and Keto Acid Biochemistry and Cellular Biology in Central Nervous System Diseases
Abstract
Branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) are essential components of many biochemical and biological processes. There are well-established pathways, such as fatty acid synthesis and oxidation, anabolic use to synthesize new proteins, and anaplerotic use to generate or sustain metabolic intermediate molecules, which we define as "classical" pathways here. Recently new "non-classical" roles for BCAAs have been discovered, most notably for leucine. Leucine has been shown to initiate protein synthesis by increasing translational protein complex activities and to suppress feeding behaviors in rats; both phenomena are at least partially mediated through the mammalian target of rapamycin (mTOR) kinase cascade. Our lab previously identified another potential non-classical pathway independent of mTOR, acting through the hypoxia inducible factor (HIF) transcriptional regulatory protein. Our goal for the first line of research for this work was to validate and further elaborate that leucine promotes HIF transcriptional activation through its 2-oxoacid derivative, alpha-ketoisocaproic acid using an in vitro glioma cell line trangenically altered to express a reporter protein for HIF-alpha degradative cycle activity. The 2-oxoacid was found to increase the half-life of the HIF-1alpha component of the HIF-1 heterodimeric complex in normal oxygen conditions and induce secretion of a known HIF-1 transcriptional protein target independent of mTOR activation.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 21, 2009
- Accession Number
- ADA539583
Entities
People
- Jeremy Henriques
Organizations
- Uniformed Services University of the Health Sciences