William Lipscomb

Molecular Dynamics in Yeast Chorismate Mutase

Wednesday, 29 June 2005
15:00 - 17:00 CEST


Vincristine. Our X-ray diffraction study (Ref.1) of vincristine methiodide in 1955-1966 established the correct absolute, and revised some of the configurations of the ten asymmetric centers. The same configuration stereochemistry occurs in the closely related vinblastine. Because of the complexity, the total synthesis was not complete until year 2004 (Ref.2 and 3).
Vinblastine treats some lymphomas, Kaposi’s sarcoma and advanced testicular and breast cancer.

Ref.1. Moncreif and Lipscomb, Acta Cryst., 21, 322 (1966).
Ref.2. Kuboyama, et al., Proc. Natl. Acad. Sci., U.S.A. 101, 11966 (2004).
Ref.3. Mangeney et al., J. Am. Chem. Soc., 101, 2243 (1979).

Captopril, an ACE inhibitor. Angiotensin converting enzyme (ACE) removes a dipeptide from the decapeptide angiotensin I (which does not raise blood pressure) to yield an octapeptide angiotensin II (which raises blood pressure). Thus an inhibitor of ACE would low abnormally high blood pressure. When Ondetti, Rubin and Cushman (Ref.4) of Squibb developed the drug captopril, the structure of ACE (a membrane bound zinc enzyme) was unknown (Ref.5).
Hence they employed our zinc enzyme, carboxypeptidase A, enlarging its active site (Ref.4). This is the first successful design of an inhibitor using the three dimensional structure of an enzyme. At the present time many effective pharmaceuticals are designed using this method.

Ref.4. Ondetti, Rubin and Cushman, Science, 1996, 441 (1977). [Ondetti died Sept. 23,2004 at age 74].
Ref.5. The structure is now known: Natesh, et al, Nature, 421, 551 (2003).

FBPase amd Type 2 Diabetes. Fructose-1,6-bisphosphatase (FBPase), the penultimate enzyme in the pathway that makes glucose, is an allosteric enzyme inhibited by adenosine monophosphate (AMP) at the allosteric site. Our interest was to elucidate the mechanism of control of the active site by binding of AMP at a distant regulatory site (Ref.6 and 7).
Then, Mark Erion of Metabasis Therapeutics and I began a collaborative project to reduce the abnormal increase of FBPase (Ref.8) shown in Type 2 Diabetics by making analogues of the inhibitor AMP. During this 15 year collaboration, we have discovered oral AMP analogues which displace AMP, have low toxicity, do not interfere with critical other AMP functions, and especially that reduce glucose levels to moderate values. Studies of effective results in the rat model are summarized in Erion, et al. Proc. Natl. Acad. Sci., submitted April 2005. Human trials are in the final stages of phase 2, and possible interactions of a promising inhibitor with metformin (a medicine for Type 2 diabetes) are under evaluation.

Ref.6. Ke, et al., Proc. Natl. Acad. Sci., U.S.A. 87, 5243 (1990).
Ref.7. Ke, et al., Biochemistry, 30, 4412 (1991).
Ref.8. Rothman, et al., Science, 254, 573 (1991).

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