Editing Collagen (section)

==Synthesis==
{{More citations needed section|date=April 2021}}
First, a three-dimensional stranded structure is assembled, mostly composed of the amino acids glycine and proline. This is the collagen precursor procollagen. Then, procollagen is modified by the addition of [[hydroxyl]] groups to the amino acids proline and [[lysine]]. This step is important for later [[glycosylation]] and the formation of collagen's triple helix structure. Because the [[hydroxylase]] enzymes performing these reactions require [[vitamin C]] as a [[Cofactor (biochemistry)|cofactor]], a long-term deficiency in this vitamin results in impaired collagen synthesis and [[scurvy]].<ref>{{cite journal | vauthors = Peterkofsky B | title = Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy | journal = The American Journal of Clinical Nutrition | volume = 54 | issue = 6 Suppl | pages = 1135S–1140S | date = December 1991 | pmid = 1720597 | doi = 10.1093/ajcn/54.6.1135s | doi-access = free }}</ref> These hydroxylation reactions are catalyzed by the enzymes [[prolyl 4-hydroxylase]]<ref>{{cite journal | vauthors = Gorres KL, Raines RT | title = Prolyl 4-hydroxylase | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 45 | issue = 2 | pages = 106–124 | date = April 2010 | pmid = 20199358 | pmc = 2841224 | doi = 10.3109/10409231003627991 }}</ref> and [[lysyl hydroxylase]]. The reaction consumes one ascorbate molecule per hydroxylation.<ref>{{cite journal | vauthors = Myllylä R, Majamaa K, Günzler V, Hanauske-Abel HM, Kivirikko KI | title = Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase | journal = The Journal of Biological Chemistry | volume = 259 | issue = 9 | pages = 5403–5405 | date = May 1984 | pmid = 6325436 | doi = 10.1016/S0021-9258(18)91023-9 | doi-access = free }}</ref> Collagen synthesis occurs inside and outside cells. 

The most common form of collagen is fibrillary collagen. Another common form is meshwork collagen, which is often involved in the formation of filtration systems. All types of collagen are triple helices, but differ in the make-up of their alpha peptides created in step 2. Below we discuss the formation of fibrillary collagen.
# '''Transcription of mRNA''': Synthesis begins with turning on genes associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3). About 44 genes are associated with collagen formation, each coding for a specific mRNA sequence, and are typically named with the "''COL''" prefix.
# '''Pre-pro-peptide formation''': The created mRNA exits the cell nucleus into the cytoplasm. There, it links with the ribosomal subunits and is translated into a peptide. The peptide goes into the endoplasmic reticulum for post-translational processing. It is directed there by a [[signal recognition particle]] on the [[endoplasmic reticulum]], which recognizes the peptide's {{Nowrap|[[N-terminal]]}} signal sequence (the early part of the sequence). The processed product is a [[Protein precursor|pre-pro-peptide]] called preprocollagen.
# '''Pro-collagen''' '''formation''': Three modifications of the pre-pro-peptide form the alpha peptide:
## The signal peptide on the N-terminal is removed. The molecule is now called ''propeptide.''
## Lysines and prolines are hydroxylated by the enzymes 'prolyl hydroxylase' and 'lysyl hydroxylase', producing hydroxyproline and hydroxylysine. This helps in cross-linking the alpha peptides. This enzymatic step requires vitamin C as a cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by three alpha peptides).
## Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl groups that were placed onto lysines, but not on prolines.
## Three of the hydroxylated and glycosylated propeptides twist into a triple helix (except for its ends), forming procollagen. It is packaged into a transfer vesicle destined for the Golgi apparatus.
# '''Modification''' '''and secretion''': In the [[Golgi apparatus]], the procollagen goes through one last post-translational modification, adding oligosaccharides (not monosaccharides as in step 3). Then it is packaged into a secretory vesicle to be secreted from the cell.
# '''Tropocollagen''' '''formation''': Outside the cell, membrane-bound enzymes called collagen peptidases remove the unwound ends of the molecule, producing tropocollagen. Defects in this step produce various collagenopathies called [[Ehlers–Danlos syndrome]]. This step is absent when synthesizing type III, a type of fibrillar collagen.
# '''Collagen fibril formation''': [[Lysyl oxidase]], a [[Copper in health|copper-dependent]] enzyme, acts on lysines and hydroxylysines, producing aldehyde groups, which eventually form covalent bonds between tropocollagen molecules. This polymer of tropocollagen is called a collagen fibril.

[[File:Tropocollagen cross-linkage lysyl oxidase (EN).svg|thumb|upright=1.3|Action of [[lysyl oxidase]]]]

===Amino acids===
Collagen has an unusual amino acid composition and sequence:
* Glycine is found at almost every third [[residue (biochemistry)|residue]].
* Proline makes up about 17% of collagen.
* Collagen contains two unusual derivative amino acids not directly inserted during [[translation (genetics)|translation]]. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.
** [[Hydroxyproline]] derived from proline
** [[Hydroxylysine]] derived from lysine – depending on the type of collagen, varying numbers of hydroxylysines are [[glycosylation|glycosylated]] (mostly having [[disaccharide]]s attached).

[[Cortisol]] stimulates [[Amide hydrolysis|degradation]] of (skin) collagen into amino acids.<ref>{{cite journal | vauthors = Houck JC, Sharma VK, Patel YM, Gladner JA | title = Induction of collagenolytic and proteolytic activities by anti-inflammatory drugs in the skin and fibroblast | journal = Biochemical Pharmacology | volume = 17 | issue = 10 | pages = 2081–2090 | date = October 1968 | pmid = 4301453 | doi = 10.1016/0006-2952(68)90182-2 }}</ref>

=== Collagen I formation ===
Most collagen forms in a similar manner, but the following process is typical for type I:

# Inside the cell
## Two types of alpha chains – alpha-1 and alpha 2, are formed during [[translation (genetics)|translation]] on ribosomes along the [[rough endoplasmic reticulum]] (RER). These peptide chains known as preprocollagen, have registration peptides on each end and a [[signal peptide]].<ref name="Dict">{{cite web |title=preprocollagen |url=https://medical-dictionary.thefreedictionary.com/preprocollagen |website=The Free Dictionary}}</ref>
## Polypeptide chains are released into the lumen of the RER.
## Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.
## [[Hydroxylation]] of lysine and proline amino acids occurs inside the lumen. This process is dependent on and consumes [[ascorbic acid]] (vitamin C) as a [[cofactor (biochemistry)|cofactor]].
## [[Glycosylation]] of specific hydroxylysine residues occurs.
## Triple alpha helical structure is formed inside the endoplasmic reticulum from two alpha-1 chains and one alpha-2 chain.
## [[Procollagen]] is shipped to the [[Golgi apparatus]], where it is packaged and secreted into the extracellular space by [[exocytosis]].
# Outside the cell
## Registration peptides are cleaved, and tropocollagen is formed by [[procollagen peptidase]].
## Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking ([[aldol reaction]]) by [[lysyl oxidase]] which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
## Collagen may be attached to cell membranes via several types of protein, including [[fibronectin]], [[laminin]], [[fibulin]], and [[integrin]].