Prolyl 4-hydroxylase and its role in collagen synthesis

doi:10.1016/0168-8278(91)90002-S

Journal of Hepatology

Volume 13, Supplement 3, 1991, Pages S2-S7

https://doi.org/10.1016/0168-8278(91)90002-S Get rights and content

Abstract

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-Glysequences. 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 α₂β₂ 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 α and β subunits, but the α subunit appears to contribute the major part. The β 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 α subunit lacks the carboxyl-terminal retention signal, one function of the β subunit in the prolyl 4-hydroxylase tetramer may be to retain the enzyme within the endoplasmic reticulum. The β subunit has proved to be a multifunctional protein as it is identical to protein disulphide isomerase, a major cellular thyroid hormone binding protein and one of the two subunits of the microsomal triglyceride transfer protein, and highly similar to the glycosylation site binding component of oligosaccharyl transferase.

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Prolyl 4-hydroxylase and its role in collagen synthesis

Abstract

J Theor Biol

Biochim Biophys Acta

J Biol Chem

Cell

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Gene

J Hepatol

Post-translational processing of procollagens

Ann NY Acad Sci

Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit

FASEB J

Molecular biology of prolyl 4-hydroxylase

Ann NY Acad Sci

Type I macrophage scavenger receptor contains α-helical and collagen-like coiled coils

Nature

Coiled-coil fibrous domains mediate ligand binding by macrophage scavenger receptor type II

Nature