EDUCATION:
Ph.D., 1987, California Institute of Technology

MEMBERSHIPS:
American Society of Biochemistry and Molecular Biology
American Chemical Society
Genetics Society of America

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Amino-terminal processing is one of the most common protein processing events, which occurs in all living cells and is essential for normal cell growth. We have discovered two distinct eukaryotic methionine aminopeptidases (MetAPs) that are responsible for this cellular event. Recently, the type-2 MetAP was found to be the molecular target for angiogenesis inhibitors, TNP-470 and ovalicin. Angiogenesis is the process of new blood vessel formation. It plays very important roles in both physiological states and a variety of pathological states. It has been demonstrated that angiogenesis is essential for the growth of solid tumors. TNP-470 was the first anti-angiogenesis compound that entered clinical trials as an anti-cancer agent. It has shown significant anti-tumor activity against 55 different types of human and animal tumors. Ovalicin, on the other hand, possesses potent immunosuppressive activity as well as anti-angiogenesis activity. The broad goal of our research project is to understand the mechanism of the amino-terminal processing of eukaryotic proteins, and its role in angiogenesis. Our short-term goals include:

1. To elucidate the role of each MetAP in amino-terminal processing of eukaryotic proteins;
2. To study the structure/function relationships between the two MetAPs;
3. To determine the molecular mechanism of the action of the angiogenesis inhibitors, TNP-470 and ovalicin
4. To develop new angiogenesis inhibitors.

With a combination of biochemistry, molecular biology, genetics, structural biology, proteomics, functional genomics, and gene therapy, we should be able to obtain valuable information regarding amino-terminal processing and angiogenesis. We also hope that we can develop new anti-cancer drugs.

Figure 1: Co-translational N-terminal Modifications. Co-translational N-terminal modifications are defined as those that occur during polypeptide synthesis on the ribosomes and are largely governed by the primary sequence of the nascent polypeptide's N-terminus (i.e., Metinit-AA2-AA3-, where AAn is amino acid in position n). Amino acid substrate requirements are listed below the resulting N-terminal modification, but do not always guarantee that the modification will occur. It is found that the majority of N-termini from mature proteins reflect these initial co-translational modifications.