Page 203 - The Toxicology of Fishes

Biotransformation in Fishes 183

UDP–Glucuronosyltransferase structure

N–terminal
signal Variable domain, Conserved domain, ER retention
peptide substrate specific UDPGA binding signal, Lys

+ –
H 3N COO
glycosylation sites
N–terminal transmembrane
conservation domain

+ H 3N lys COO – Cytoplasm lys COO –

ER

Lumen + H 3N
cleavage

FIGURE 4.7 Structure and organization of UDP–glucuronosyltransferases.

Phase II Enzymes

UDP-Glucuronosyltransferases
Overview
The UDP-glucuronosyltransferases (UGTs) represent a major group of phase II conjugating enzymes.
Glucuronidation is principally a characteristic feature of vertebrates; invertebrates tend to prefer to utilize
glycosylation. Glucuronidation is the major pathway for the conversion (and inactivation) of both
endogenous and exogenous compounds to polar, water-soluble compounds that are then excreted in the
bile (compounds > 350 MW) or urine (compounds < 300 MW). The UGTs are active in the metabolism
of endogenous compounds such as steroid hormones, thyroid hormones, and waste products such as
bilirubin (Dutton, 1990). In addition, an important role is played in the biotransformation of natural
toxins and anthropogenic toxicants that are absorbed into the organism. Because of their importance in
the breakdown of therapeutic drugs, UGTs are extensively researched in the medical and pharmaceutical
fields (Parkinson, 2001). This explains why so much is known about UGTs in mammalian systems,
while research on UGTs in lower vertebrates and invertebrates is much more limited.
The glucuronosyltransferases are located in the endoplasmic reticulum (ER), with the active site facing
inward into the lumen of the ER (Figure 4.7). The various isozymes have a common C-terminal, which
anchors the enzyme in the membrane of the ER. This brings them in close proximity to phase I enzymes,
such as CYP1A, which are also located on the ER; thus, phenolic phase I metabolites formed by CYPs
can immediately be conjugated by the neighboring phenol-type UGT (UGT1A6). It has even been
suggested that direct contact between CYP1A1 and UGT1A6 occurs and that these protein–protein
interactions enhance the activity of the glucuronidation enzyme (Taura et al., 2004).