Conjugase

Folate antagonists (eg, methotrexate and certain antiepileptics) are used ia treatment for various diseases, but their adininistration can lead to a functional folate deficiency. Folate utilization can be impaired by a depletion of ziac (see Zinc compounds). In humans, the intestinal bmsh border folate conjugase is a ziac metaHoenzyme (72). One study iadicates that the substantial consumption of alcohol, when combiaed with an iaadequate iatake of folate and methionine, may iacrease the risk of colon cancer (73). Based on this study, it is recommended to avoid excess alcohol consumption and iacrease folate iatake to lower the risk of colon cancer. 

Many of the phase 1 enzymes are located in hydrophobic membrane environments. In vertebrates, they are particularly associated with the endoplasmic reticulum of the liver, in keeping with their role in detoxication. Lipophilic xenobiotics are moved to the liver after absorption from the gut, notably in the hepatic portal system of mammals. Once absorbed into hepatocytes, they will diffuse, or be transported, to the hydrophobic endoplasmic reticulum. Within the endoplasmic reticulum, enzymes convert them to more polar metabolites, which tend to diffuse out of the membrane and into the cytosol. Either in the membrane, or more extensively in the cytosol, conjugases convert them into water-soluble conjugates that are ready for excretion. Phase 1 enzymes are located mainly in the endoplasmic reticulum, and phase 2 enzymes mainly in the cytosol. 

Conversion of epoxides (arene oxides) into phenols is spontaneous. The conversion of epoxides into dihydrodiols is catalyzed by EH (EC 4.2.1.63). Hydroxyl containing PAHs can act as substrates for conjugases (C) (UDP glucuronsyl transferase (EC 2.4.1.17) and phenol sulphotransferase (EC 2.8.2.1)). This pathway usually leads to inactive excretable products. Epoxides are scavenged by GSH and the reaction is catalyzed by GSHt (EC 2.5.1.18). When GSH is depleted and/or the other pathways are saturated, epoxides of dihydrodiols (particularly 7,8-diol-9,10-epoxides in the case of BP) and phenol metabolites react with cellular macromolecules such as DNA, RNA, and protein. If repair mechanisms are exceeded the detrimental effects of PAH may result. 

Wing, J. P., et al., Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis. Nat Cell Biol, 2002, 4(6), 451-6. 

T Tamura, Y Mizuno, KE Johnston, RA Jacob. Food folate assay with protease, a-amylase, and folate conjugase treatments. J Agric Food Chem 45 135-139, 1997. 

Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Dietary folates, however, consist primarily of polyglutamate forms of N 5-methyltetrahydrofolate. Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme -1-glutamyl transferase ("conjugase") within the brush border of the intestinal mucosa. 

Many of the water-soluble vitamins are present in foods bound to proteins, and their release may require either the action of gastric acid (as for vitamin B12, Section 10.7.1) or specific enzymic hydrolysis [e.g., the action of conjugase to hydrolyze folate conjugates (Section 10.2.1) and the hydrolysis of biocytinto release biotin (Section 11.2.3)]. 

Because conjugase is a zinc metallo-enzyme, zinc deficiency can impair the absorption of conjugated food folates, but not folate monoglutamate. 

Conjugase responds rapidly to zinc depletion and repletion, and it has been suggested that the absorption of a test dose of folate polyglutamates may provide a sensitive index of zinc nutritional status (Canton and Cremin, 1990). The absorption of folate monoglutamates (from pharmaceutical preparations or foods) is not affected. 

Free folate, released by conjugase action, is absorbed by a carrier-mediated mechanism in the jejunum. However, the folate in mUk is mainly bound to a specific binding protein (which has been used in radioligand binding assays for folate) the protein-folate complex is absorbed intact, mainly in the ileum, by a mechanism that is distinct from the j ejunal transport system for free folate. The biological availability of folate from miLk, or of folate from diets to which mUk has been added, is considerably greater than that of unbound folate, whereas that of folate from cereal foods, or of free folic acid taken with cereal foods, is lower. 

DiphenyUiydantoin and other anticonvulsants impair the intestinal absorption of folates. This may be by inhibition of intestinal conjugase however, the evidence from various studies is conflicting. 

---