Excessive accumulation of
collagen in the extracellular matrix has a crucial role in
fibrosis. Thus pharmacological inhibition of
collagen deposition is likely to be beneficial for patients suffering from fibrotic disorders such as
liver cirrhosis.
Prolyl 4-hydroxylase catalyzes the formation of
4-hydroxyproline in
collagens and other
proteins with
collagen-like amino acid sequences by the hydroxylation of
proline residues in -X-
Pro-Gly- sequences. The reaction products,
4-hydroxyproline residues, serve to stabilize the
collagen triple helices under physiological conditions. Conversely,
collagen chains that contain no
4-hydroxyproline cannot fold into triple helical molecules that are stable at body temperature. The
prolyl 4-hydroxylase reaction therefore seems to be a particularly suitable target for the pharmological regulation of excessive
collagen formation. The reaction catalyzed by
prolyl 4-hydroxylase requires Fe2+,
2-oxoglutarate, O2 and ascorbate and involves an oxidative decarboxylation of
2-oxoglutarate. The active
enzyme is an alpha 2 beta 2 tetramer that consists of two types of inactive monomer and has two catalytic sites. Some parts of the catalytic sites may be built up cooperatively of both the alpha and beta subunits, but the alpha subunit appears to contribute the major part. The beta subunit contains the carboxyl-terminal tetrapeptide sequence -
Lys-Asp-Glu-Leu which is essential for the retention of a
polypeptide within the lumen of the endoplasmic reticulum. Since the alpha subunit lacks the carboxyl-terminal retention signal, one function of the beta subunit in the
prolyl 4-hydroxylase tetramer may be to retain the
enzyme within the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 250 WORDS)