Lysine collagen synthesis

C Ascorbic acid Coenzyme in hydroxylation of proline and lysine in collagen synthesis antioxidant enhances absorption of iron Scurvy—impaired wound healing, loss of dental cement, subcutaneous hemorrhage... 

Proline/lysine hydroxylase (mammalian) mononuclear iron complement Clq and collagen synthesis Substrate carbanion and iron bound hydroxyl 3.2.2. 

Progressive fibro-proliferative diseases (e.g. liver cirrhosis, pulmonary fibrosis, rheumatoid arthritis) result in a dramatic increase in collagen synthesis [227], This is preceded by inflammation that correlates with an increased activity of proline and lysine hydroxylase [228], Although they are unlikely to be the primary initiators of these diseases the increased activities of these enzymes may cause other problems. For example, in vitro the enzyme can turn over in the absence of a peptide substrate (but the presence of the 2-oxoglutarate cofactor). In this case stoichiometric amounts of ascorbate are required, probably to reduce the ferryl ion back to ferrous [229]. In vivo, lower concentrations of ascorbate are utilised [229,230], possibly to reactivate the enzyme after a non-productive activation (for example in the presence of a peptide that can bind to the active site, but cannot be hydroxylated). As the amount of proline-hydroxylase activity increases in the fibro-proliferative diseases, the concentration of ascorbate might not be sufficient to reduce these inactive complexes, resulting in the formation of potentially reactive ferryl intermediates. 

Most of the other clinical signs of scurvy can be accounted for by effects of deficiency on collagen synthesis as a result of impaired proUne and lysine hydroxylase activity (Section 13.3.3). 

The copper metalloenzymes are involved in oxygen-using reactions. These enzymes include cytochrome c oxidase (respiratory chain), lysyl oxidase (collagen synthesis), and dopamine [3-hydroxylase (neurotransmitter synthesis). Lysyl oxidase is a small protein with a molecular weight of 32 kDa. This enzyme contains an unusual modification, namely cross-linking between two different parts of its polypeptide chain. The cross-linked region consists of a structure called lysine tyrosylquinone (Klinman, 1996). Two amino acids are involved in this cross-linked structure, and these are Lys 314 and Tyr 349. Lysine tyrosylquinone is used as a cofactor and is necessary for the catalytic activity of the enzyme. Other copper metalloenzymes contain a related cofactor, namely 2,4,5-tiihydrox5q5henylalanine (topaquinone, TPQ). Serum amino oxidase is a copper metalloenzyme that contains TPQ. TPQ consists of a modified residue of phenylalanine. The copper in the active site of the enzyme occurs immediately adjacent to the TPQ cofactor. 

A. The patient exhibits the classic symptoms of scurvy, a deficiency in vitamin C. In addition to being an important biological antioxidant, ascorbic acid is required for the hydroxylation of proUne and lysine residues of procollagen in the synthesis of collagen. A deficiency leads to defects in collagen synthesis, which adversely affects the intercellular cement substances in connective tissue, bones, and dentin. 

L-ascorbic acid deficiency results in reduced hydroxylation of proline and lysine, thus destabilizing the collagen triple helix, and the impaired collagen synthesis leads mainly to defective connective tissue. 

Most of the other clinical signs of scurvy can be accounted for by the effects of ascorbate deficiency on collagen synthesis, as a result of impaired proline and lysine hydroxylase activity. Depletion of muscle carnitine (section 5.5.1), as a result of impaired activity of trimethyllysine and y-butyrobetaine hydroxylases, may account for the lassitude and fatigue that precede clinical signs of scurvy. 

Lysine, like most other AAs, is a building block of body protdns. Among the indispensable AAs, lysine is present in the greatest amounts, at 93.0 and 38 mmol/dl in tissues and serum, respectively (see Table 15.3). Carnitine, a compound responsible for transport of long-chain fatty adds into the mitochondria for oxidation, is synthesized in the liver and kidneys from lysine and methionine. Lysine is also required for collagen synthesis and may be central to bone health. - Lysine s effects... 

A number of iron-containing, ascorbate-requiring hydroxylases share a common reaction mechanism in which hydroxylation of the substrate is linked to decarboxylation of a-ketoglutarate (Figure 28-11). Many of these enzymes are involved in the modification of precursor proteins. Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen to collagen, and prohne hydroxylase is also required in formation of osteocalcin and the Clq component of complement. Aspartate P-hydroxylase is required for the postsynthetic modification of the precursor of protein C, the vitamin K-dependent protease which hydrolyzes activated factor V in the blood clotting cascade. TrimethyUysine and y-butyrobetaine hydroxylases are required for the synthesis of carnitine. 

Ascorbic acid or vitamin C is found in fruits, especially citrus fruits, and in fresh vegetables. Man is one of the few mammals unable to manufacture vitamin C in the liver. It is essential for the formation of collagen as it is a cofactor for the conversion of proline and lysine residues to hydroxyproline and hydroxylysine. It is also a cofactor for carnitine synthesis, for the conversion of folic acid to folinic acid and for the hydroxylation of dopamine to form norepinephrine. Being a lactone with two hydroxyl groups which can be oxidized to two keto groups forming dehydroascorbic acid, ascorbic acid is also an anti-oxidant. By reducing ferric iron to the ferrous state in the stomach, ascorbic acid promotes iron absorption. 

Hydroxyproline and hydroxylysine occur most noticeably in collagen. These are formed by modification of proline and lysine residues by specific enzymes after synthesis of the collagen chains. It is interesting to note that proly/hydroxylase, which hydroxylates proline, requires ascorbate (vitamin C) as a coreactant. Other chemical modifications known to occur commonly are the attachment of sugars (glycosylation) to asparagine, serine, and threonine residues and the phosphorylation of serine. Chemical modifications are also associated with the transport of proteins out of the cells in which they are synthesized. 

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