This part of Hemimorphitara moves one reaction at a time: how lysyl oxidase and prolidase do their work, which cross-bridges arise in fibers, and how the EU statement on manganese, like the one on copper, is meant to be read on its own.
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A collagen molecule passes through several locations before it becomes part of a load-bearing fibril, and later on it is taken apart into its building blocks again. The table lines up the stages that matter for this page. Two of them depend on one of the trace elements described here; the rest are included for orientation.
| What happens | Where it happens | Catalyzing enzyme | Metal in the enzyme |
|---|---|---|---|
| Assembly of the protein chains | ribosomes on the endoplasmic reticulum | none in the strict sense | not covered here |
| Twisting into a triple helix | endoplasmic reticulum | folding helpers | not covered here |
| Removal of the end pieces | just outside the cell | procollagen proteinases | not covered here |
| Oxidation of selected lysine residues | surface of the growing fibril | lysyl oxidase | copper |
| Formation of the cross-bridges | between neighboring molecules | proceeds on its own | no enzyme involved |
| Cleavage of proline-containing dipeptides | cytoplasm | prolidase | manganese |
Freshly assembled collagen molecules cling to each other only through weak non-covalent bonds. The covalent cross-bridges that form over the following days tie the end of one molecule to the helix of the staggered molecule lying beside it. In this way a bundle of parallel strands becomes a thread that spreads pulling forces over its entire length.
The matrix is not a finished structure. Cells keep dissolving older fibrils and replacing them. Roughly a quarter of the amino acids in collagen are proline or hydroxyproline, so breakdown produces an unusually large number of fragments carrying this ring. How the body puts them back to use is the subject of the section on prolidase.
Lysyl oxidase is a small enzyme that cells secrete. It is made as a longer precursor, and only after a propeptide has been cut away outside the cell does it become fully active. Related enzymes from the same family follow the same principle but differ in their other regions.
Most enzymes that oxidize amines take in their organic cofactor from outside, as a vitamin derivative. Lysyl oxidase makes its own: a tyrosine in its chain is oxidized and fused to a lysine in the same chain. The product is called lysyl tyrosylquinone, or LTQ for short. This self-assembly already requires the copper ion, and in the finished enzyme the ion sits right next to the LTQ.
Copper does not wait until the matrix to meet the enzyme. In the late section of the Golgi apparatus, the copper ATPase ATP7A pumps ions into the interior of the membrane vesicles where newly made lysyl oxidase waits for its trip outside. The enzyme therefore leaves the cell with its metal already on board.
In the active site, oxygen removes the amino group at the tip of a lysine side chain. The result is allysine, which carries an aldehyde group; hydroxylysine yields hydroxyallysine in the same way. Ammonia and hydrogen peroxide exit the enzyme as by-products. The condensation reactions that come next run without a catalyst and vary from one fiber protein to another.
| Fiber protein | Typical mature cross-bridge | Side chains taking part |
|---|---|---|
| Collagen | pyridinoline, deoxypyridinoline | three, from lysine or hydroxylysine |
| Collagen (early form) | two-way aldimines and ketoamines | two |
| Elastin | desmosine, isodesmosine | four lysine residues, three of them oxidized beforehand |
| Elastin | lysinonorleucine | two |
Desmosine and isodesmosine are found almost only in elastin. Their pyridinium ring joins as many as four chains at a single point, which accounts for how the elastin network can stretch without falling apart. The authorized statement on copper reads:
“Copper contributes to maintenance of normal connective tissues”
EU-authorized wording · Regulation (EU) No 432/2012
Prolidase works in the cytoplasm, at the far end of the path that lysyl oxidase set in motion. Its substrates are dipeptides whose second amino acid is proline or hydroxyproline. The technical name for them is imidodipeptides.
Strictly speaking, proline is not an amino acid but an imino acid: its nitrogen is part of a five-membered ring. The peptide bond to that nitrogen is bulkier than usual and can adopt two spatial positions. Ordinary dipeptidases recognize this shape poorly. Without an enzyme specialized for it, the proline-containing two-unit pieces would go to waste.
Structural studies show the human enzyme as a pair of two identical subunits. Each one has an active site with two metal positions, which are filled with manganese under physiological conditions. The ions hold a hydroxide ion between them. It attacks the carbonyl group of the peptide bond while the metals steady the intermediate that forms. The dipeptide breaks apart, and both amino acids are set free.
| Manganese-dependent enzyme | What gets split or joined | Connection to the matrix |
|---|---|---|
| Prolidase | splits dipeptides ending in proline or hydroxyproline | frees proline from collagen breakdown |
| several glycosyltransferases | attach activated sugars to growing chains | sugar chains of the proteoglycans |
| hyaluronan synthases | link two sugar units in alternation | hyaluronic acid in the filler; magnesium also works here |
For several glycosyltransferases, laboratory experiments show that manganese can be partly swapped for other divalent ions. As a result, which ion is actually bound in tissue cannot be named with the same certainty for every enzyme. For manganese, the EU has authorized this statement:
“Manganese contributes to the normal formation of connective tissue”
EU-authorized wording · Regulation (EU) No 432/2012
Regulation (EU) No 432/2012 lists the health claims that may be used within the European Union. Each one rests on an opinion from the European Food Safety Authority and comes with conditions, such as a minimum amount in the product. For connective tissue, the regulation contains these entries:
Manganese entry
“Manganese contributes to the normal formation of connective tissue”
EU-authorized wording · Regulation (EU) No 432/2012
Copper entry
“Copper contributes to maintenance of normal connective tissues”
EU-authorized wording · Regulation (EU) No 432/2012
The sentence on manganese speaks of formation; the sentence on copper speaks of maintenance. The two wordings come out of separate assessment procedures and appear here unchanged. They cannot be merged into one shared statement, nor can either be carried over to the other element. Both describe a normal state and no change going beyond it.
Labels in the EU express mineral amounts against the EU reference intakes in Annex XIII of Regulation (EU) No 1169/2011: 2 mg per day for manganese, 1 mg per day for copper. The figures below are rounded and can differ noticeably depending on origin and processing.
| Ingredient, per 100 g | Manganese | Copper |
|---|---|---|
| Hazelnut kernels | about 6 mg | about 1.7 mg |
| Rolled oats | about 4 mg | about 0.4 mg |
| Cocoa powder, low in fat | about 3.8 mg | about 3.8 mg |
| Lentils, dried | about 1.4 mg | about 0.8 mg |
The number of bridges depends on how much lysyl oxidase the cells produce, how many lysine residues on the fibril are within reach and how much time the reaction gets. The copper ion is a prerequisite for an active enzyme, not a dial that pushes the number of bridges higher. The authorized statement does not describe any increase either.
No. Collagenases belong to the matrix metalloproteinases and make the first cut in the intact triple helix outside the cell. Prolidase steps in only at the very end of breakdown, inside the cell, and splits nothing larger than two-unit pieces. Both enzymes are part of the same cycle, yet they handle entirely different jobs within it.
Each wording was settled in a procedure of its own for that particular element. The enzymes on this page explain the biochemical background, but they are not what lies behind the regulation’s choice of words. For that reason Hemimorphitara only ever reproduces each sentence together with its own element.
The account relies on textbooks of biochemistry and matrix biology, on published crystal structures of human prolidase and on review articles about the lysyl oxidase family. The wording of the two statements is taken from Regulation (EU) No 432/2012 as published in the Official Journal of the European Union.
Reaction schemes for lysyl oxidase and prolidase, two enzyme tables and the full wording of both EU statements, each one assigned to its own element.
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