| The two endogenous antagonists, Agouti Signaling Protein (ASIP) and Agouti Related Protein (AgRP), have much in common, but they vary quite dramatically in physiology. Structurally the C-terminus of both proteins are highly homologous, both act at similar 7TM-GPCRs known collectively as the melanocortin receptors, but the in vivo function of the two antagonists are entirely dissimilar. ASIP regulates pigment type switching, while AgRP controls satiety. This dissertation demonstrates the first ever total chemical synthesis of AgRP from fish. It also establishes, for the first time, a bacterial expression system for ASIP procurement as well as validates a robust technique of ASIP production. In addition it provides proof that the three contiguous amino acid residues, Arg-Phe-Phe, from the active loop of AgRP are indeed responsible for much of the pharmacology. Lastly it helps illuminate the mechanism of melanocortin 4 receptor auto-activation. |
