Substrate specificity, monooxygenases

Figure 3 Illustration of overlapping substrate specificities of four BVMOs. Cyclohexanone monooxygenase (CHMO), cyclopentanone monooxygenase (CPMO), 4-hydroxyacetophenone monooxygenase (HAPMO) and phenylacetone monooxygenase (PAMO). For each enzyme, several typical substrates are...

Rasche ME, MR Hyman, DJ Arp (1991) Factors limiting aliphatic chlorocarbon degradation by Nitrosomonas europaea cometabolic inactivation of ammonia monooxygenase and substrate specificity. Appl Environ Microbiol 57 2986-2994. 

Cytochrome P450-type monooxygenase systems, which have a generally low substrate specificity, are widely distributed in the species of fish used for toxicity testing (Funari et al. 1987). 

The 4-methoxybenzoate monooxygenase from Pseudomonas putida shows low substrate specificity. Although it introduces only a single atom of oxygen into 3-hydroxy- and 4-hydroxybenzoate, it accomplishes the conversion of 4-vinylbenzoate into the corresponding side-chain diol (Wende et al. 1989). 

Kamerbeek NM, All Olsthoorn, MW Fraaije, DB Janssen (2003) Substrate specificity and enantioselectivity of 4-hydroxyacetophenone monooxygenase. Appl Environ Microbiol 69 419-426. 

Most oxidation reactions are catalyzed by cytochrome P450 systems (see p. 318). These monooxygenases are induced by their substrates and show wide specificity. The substrate-specific enzymes of the steroid metabolism (see p. 376) are exceptions to this. 

The flavin monooxygenases (FMOs) are a family of five enzymes (FMO 1-5) that operate in a manner analogous to the cytochrome P450 enzymes in that they oxidize the drug compound in an effort to increase its elimination. Though they possess broad substrate specificity, in general they do not play a major role in the metabolism of drugs but appear to be more involved in the metabolism of environmental chemicals and toxins. 

Ziegler DI (1988) Flavin-containing monooxygenases catalytic mechanism and substrate specificities. Dmg Metab Rev 19(l) l-32... 

Burrows, K. J., A. Cornish, D. S. Scott, and I. J. Higgins, Substrate specificities of the soluble and particulate methane monooxygenases of Methylosinus trichosporium OB3b. Mol. Microbiol., 6, 335-342 (1984). 

One important finding from purification studies as well as cloning and expressing of individual isoforms is that the lack of substrate specificity of microsomes for monooxygenase activity is not an artifact caused by the presence of several specific cytochromes. Rather, it appears that many of the cytochromes isolated are still relatively nonspecific. The relative activity toward different substrates does nevertheless vary greatly from one CYP isoform to another even when both are relatively nonspecific. This lack of specificity is illustrated in Table 7.2, using human isoforms as examples. 

Tertiary amines such as trimethylamine and dimethylamine had long been known to be metabolized to A -oxides by a microsomal amine oxidase that was not dependent on CYP. This enzyme, now known as the microsomal flavin-containing monooxygenase (FMO), is also dependent on NADPH and 02, and has been purified to homogeneity from a number of species. Isolation and characterization of the enzyme from liver and lung samples provided evidence of clearly distinct physicochemical properties and substrate specificities suggesting the presence of at least two different isoforms. Subsequent studies have verified the presence of multiple forms of the enzyme. 

Two different enzyme systems have been described, one uses cytochrome P-450 to activate oxygen whereas the other employs flavin adenine dinucleotide (FAD). Both the cytochrome P-450 and the flavin monooxygenase systems have broad substrate specificities and oxidize and oxygenate a variety of organic nitrogen or sulfur compounds. The enzymes have a widespread distribution and have been detected in animals, plants, fungi and bacteria. Their function appears to be primarily one of detoxification of xenobiotics. Microbial enzymes... 

A good example of substrate specificity in enzyme action is the metabolism of juvenile hormone (JH) analogs by insects. In a series of experiments summarized in Table 9.7 to 9.10, the activity of esterases and microsomal monooxygenases from three dipterans against 12... 

---