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International
Tables for Crystallography Volume F Crystallography of biological macromolecules Edited by M. G. Rossmann and E. Arnold © International Union of Crystallography 2006 |
International Tables for Crystallography (2006). Vol. F. ch. 1.3, p. 24
Section 1.3.4.4. Drug metabolism and crystallography
aBiomolecular Structure Center, Department of Biological Structure, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7742, USA |
As soon as a drug enters the body, an elaborate machinery comes into action to eliminate this foreign and potentially harmful molecule as quickly as possible. Two steps are usually distinguished in this process: phase I metabolism, in which the drug is functionalized, and phase II metabolism, in which further conjugation with endogenous hydrophilic molecules takes place, so that excretion via the kidneys can occur. Whereas this `detoxification' process is essential for survival, it often renders promising inhibitors useless as drug candidates. Hence, structural knowledge of the proteins involved in metabolism could have a significant impact on the drug development process.
Thus far, only the structures of a few proteins crucial for drug distribution and metabolism have been elucidated. Human serum albumin binds hundreds of different drugs with micromolar dissociation constants, thereby altering drug levels in the blood dramatically. The structure of this important carrier molecule has been solved in complex with several drug molecules and should one day allow the prediction of the affinity of new chemical entities for this carrier protein, and thereby deepen our understanding of the serum concentrations of new candidate drugs (Carter & Ho, 1994![[link]](/graphics/greenarr.gif)
; Curry et al., 1998; Sugio et al., 1999). Human oxidoreductases and hydrolases of importance in drug metabolism with known structure are: alcohol dehydrogenase (EC 1.1.1.1) (Hurley et al., 1991), aldose reductase (EC 1.1.1.21) (Wilson et al., 1992), glutathione reductase (NADPH) (EC 1.6.4.2) (Thieme et al., 1981), catalase (EC 1.11.1.6) (Ko et al., 2000), myeloperoxidase (EC 1.11.1.7) (Choi et al., 1998) and beta-glucuronidase (EC 3.2.1.31) (Jain et al., 1996). Recently, the first crystal structure of a mammalian cytochrome P-450, the most important class of xenobiotic metabolizing enzymes, has been reported (Williams et al., 2000).
Of the conjugation enzymes, only glutathione S-transferases (EC 2.5.1.18) have been characterized structurally: A1 (Sinning et al., 1993), A4-4 (Bruns et al., 1999), MU-1 (Patskovsky et al., 1999), MU-2 (Raghunathan et al., 1994), P (Reinemer et al., 1992) and THETA-2 (Rossjohn, McKinstry et al., 1998). Tens of structures await elucidation in this area (Testa, 1994).
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