Prolyl 4 hydroxylase

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Prolyl 4 hydroxylase
Prolyl 4 hydroxylase
Mass / length primary structure 534/535/544 amino acids ( Homo sapiens )
Secondary to quaternary structure Tetramer made up of two α and two β subunits
Cofactor vitamin C
Enzyme classification
EC, category 1.14.11.2 ,  dioxygenase
Response type Hydroxylation
Substrate Peptidyl proline + α-ketoglutarate + O 2
Products Peptidyl- hydroxyproline + succinic anhydride + CO 2
Occurrence
Parent taxon Eukaryotes (Eucaryota)

The prolyl 4-hydroxylase (4-PH) (also: Procollagenprolin dioxygenase , EC  1.14.11.2 ) is a enzyme complex in eukaryotes (Eucaryota) formed in tissue animals or vertebrates the hydroxylation of prolyl residues in proteins catalyzed . This is a post-translational modification . It is essential for the biosynthesis of collagen .

Catalyzed reaction

With the help of molecular oxygen (O 2 ), certain prolyl residues of the physiological substrate collagen are hydroxylated. In each case, one oxygen atom goes to α-ketoglutarate , which (through decarboxylation) becomes succinate , the other to the prolyl radical, which becomes 4-hydroxyprolyl . Two different reactions can take place at the same time:

  • the prolyl hydroxylation without ascorbate:
Prolyl procollagen + α-ketoglutarate + O 2 4-hydroxyprolyl procollagen + succinate + CO 2
  • the uncoupled decarboxylation of ketoglutarate with ascorbate (with and without the presence of the prolyl residue):
(Prolyl procollagen +) α-ketoglutarate + ascorbate + O 2 (prolyl procollagen +) succinate + CO 2 + dehydroascorbate

In the first reaction, both atoms of an oxygen molecule are not transferred to the same substrate, but to two different ones.

structure

It is a tetramer made up of two α and two β subunits. In humans, the α-subunit can be encoded by three possible paralog genes , whereby there are still isoforms from alternative splicing in each case . The second subunit is a protein disulfide isomerase which, when it participates in the post-translational modification of proteins , can act as a chaperone in high concentration . It is also a subunit of the MTTP protein .

Surname gene Protein size
(aa)		 UniProt OMIM comment
4-PH α-1 P4HA1 534 P13674 176710 ER lumens. Isoforms 1,2. EC  1.14.11.2
4-PH α-2 P4HA2 514 O15460 600608 ER lumens. Isoforms IIa, IIb. EC  1.14.11.2
4-PH α-3 P4HA3 525 Q7Z4N8 608987 ER lumen, placenta , liver , fetal tissue. Isoforms 1,2. EC  1.14.11.2
PDI P4HB 491 P07237 176790 ubiquitous, multifunctional, EC  5.3.4.1

Enzyme and coenzymes

Prolyl hydroxylase is a mixed functional hydroxylase or dioxygenase .

In their active center there is reduced iron (Fe 2+ ), which can briefly release an electron.

Cofactors: α-ketoglutarate is required for activity, ascorbate for regeneration (see ascorbic acid # Physiological significance ). In addition, the substrate and molecular oxygen and the absence of specific inhibitors are required for the activity.

Occurrence and expression

Prolyl hydroxylases are necessary for the biosynthesis of collagen, so they occur in all vertebrate fibroblast cells and connective tissue cells as well as many other cells, but are not expressed in all body cells .

Stimulation / inhibition

The enzyme activity can be stimulated by bleomycin .

Prolyl hydroxylases can be specifically inhibited by poly (L-proline), by poly (ADP-ribose), Roxadustat or by erythropoietin (EPO, see Erythropoietin #inductors of EPO synthesis ) .

literature

  • RA Berg, DJ Prockop: Affinity column purification of protocollagen proline hydroxylase from chick embryos and further characterization of the enzyme . In: J. Biol. Chem. 248 (1973), pp. 1175-1182, PMID 4346946 .
  • JJ Hutton Jr., AL Tappel, S. Udenfriend: Cofactor and substrate requirements of collagen proline hydroxylase . In: Arch. Biochem. Biophys. 118, pp. 231-240 (1967).
  • KI Kivirikko, Y. Kishida, S. Sakakibara, J. Prockop: Hydroxylation of (X-Pro-Gly) n by protocollagen proline hydroxylase. Effect of chain length, helical conformation and amino acid sequence in the substrate . In: Biochim. Biophys. Acta 271 (1972), pp. 347-356, PMID 5046811 .
  • KI Kivirikko, DJ Prockop: Purification and partial characterization of the enzyme for the hydroxylation of proline in protocollogen . In: Arch. Biochem. Biophys . 118 (1967), pp. 611-618.

Individual evidence

  1. ↑ References in: Arabidopsis thaliana , Caenorhabditis elegans , Drosophila melanogaster , Homo sapiens , Paramecium bursaria , by
    J. Myllyharju: Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis . In: Matrix Biol. . 22, 2003, pp. 15-24.
  2. ↑ L Kukkola, R Hieta, KI Kivirikko, J Myllyharju: Identification and characterization of a third human, rat, and mouse collagen prolyl 4-hydroxylase isoenzyme . In: J. Biol. Chem. . 278, No. 48, November 2003, pp. 47685-93. doi : 10.1074 / jbc.M306806200 . PMID 14500733 .
  3. ↑ KI Kivirikko, R Myllylä, T Pihlajaniemi: Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit . In: FASEB J . . 3, No. 5, March 1989, pp. 1609-17. PMID 2537773 .
  4. ↑ UniProt P07237
  5. ↑ K. Takeda, S. Kawai, F. Kato, T. Tetsuka, K. Konno: Stimulation of prolyl hydroxylase activity by bleomycin . In: Journal of Antibiotics . tape 31 , no. 9 , 1978, p. 884-887 , PMID 81830 .
  6. ↑ DF Counts, GJ Cardinale, S. Udenfriend: Prolyl hydroxylase half reaction: peptidyl prolyl-independent decarboxylation of alpha-ketoglutarate. In: Proceedings of the National Academy of Sciences . tape 75 , no. 5 , 1978, p. 2145-2149 , PMID 209453 .
  7. ↑ MZ Hussain, QP Ghani, TK Hunt: Inhibition of prolyl hydroxylase by poly (ADP-ribose) and phosphoribosyl-AMP. Possible role of ADP-ribosylation in intracellular prolyl hydroxylase regulation . In: The Journal of Biological Chemistry . tape 264 , no. 14 , April 15, 1989, pp. 7850-7855 , PMID 2542248 .