Pathways and Networks of Nuclear Receptors and Modeling of Syndrome X

Abstract

Nuclear receptors form a superfamily of proteins that function as ligand-activated transcription factors. One class of these receptors is hormone receptors to which steroid/thyroid hormones/retinoid bind, and thus is involved in endocrine system disorders, such as breast and prostate cancer. Another class of receptors were called orphan receptors because their ligands were unknown. Recently, the ligands were identified for some of these receptors, revealing their functions as metabolic sensors. Moreover the relationship between orphan receptors and various metabolic disorders that are now collectively called Syndrome X was unveiled. Syndrome X is lifestyle related health disorders including obesity, diabetes, hyperlipidemia, hypertension, and atherosclerosis. Orphan receptors also act as defense sensors against xeno- and endobiotics, for their target genes include drug and xenobiotic chemical metabolic enzymes (cytochromes P-450) and transporters. The nuclear receptors and Syndrome X offer a wide range of chemical computing and bioinformatics research topics: receptor modeling, ligand-receptor docking, interaction of DNA and receptor dimer complex, identification of target genes, cis-regulatory elements, product proteins, and the resultant pathways/networks, and modeling and simulation of the pancreatic beta-cell, adipocyte, insulin signaling, and obesity. The author reviews the state-of-the-art of nuclear receptor and Syndrome X research from chemical computing and bioinformatics viewpoint, and proposes a project, called Nuclear Receptor and Syndrome X (NR-SX) Project, which is a possible killer application of chemical computing and bioinformatics in the genomic era.