Hydroxyproline metabolism

Further reading Scriver, C.R. (1978). Disorders of proline ar hydroxyproline metabolism. In Stanbury, J.E... 

Further reading-. Scriver, C.R. (1978). Disorders of proline and hydroxyproline metabolism. In Stanbury, J.B., Wyngaarden, J.B. and Fredrickson, D.S. (eds.) The Metabolic Basis of Inherited Disease. 4th Edn., p. 336. (New York McGraw-Hill)... 

Figure 30-11. Intermediates in i-hydroxyproline catabolism. (a-KA, a-keto acid a-AA, a-amino acid.) Numerals identify sites of metabolic defects in hyperhydroxyprolinemia and type II hyperprolinemia.

Cell metabolism induction. Methanol extract of STE, in collagen-producing cells, stimulated glycolysis by 80% in cartilage but was not affected in the other tissues. Medium alkaline phosphatase activity was unaffected. In the frontal bone and cartilage, [ H]hydroxyproline and [ H]proline contents were decreased. Neither was affected in the aorta. 

Most of the fluoro derivatives of proline described in the literature are fluorinated in the 4 position. 4-Fluoroprolines are able to mimic 4-hydroxyproline, present in some proteins and polypeptides. On the other hand, 4-fluorination could suppress oxidative metabolism or modified ring conformation of ligands.The labeled analogues may be used as probes in PET (positron emission tomography) for localization of tumors... 

Despite the divergent results obtained with different preparations of tritiated proline, we have found that the ratio of the tritiated water formed to the tritiated hydroxyproline formed is constant for a given batch of tritiated proline. Since in the carrageenin tumor system there is a definite relationship between the formation of tritiated water and tritiated hydroxyproline, this system should be of value in obtaining definitive results when appropriately labeled prolines are available. This is apparently not true for the chick embryo, in which there is a considerable metabolism of proline to other products and therefore a much greater formation of tritiated water (23). 

Proteins of all organisms are based on the 20 common amino acids, generally referred to as protein amino acids. In some cases, these amino acids are modified post-translationally, e.g. the hydroxyproline moieties in several cell wall proteins. Apart from these protein amino acids, numerous other amino acids occur in plants. Some of them are known to be intermediates in various pathways of primary metabolism, e.g. ornithine as a metabolite in arginine bios)m-thesis, 8-aminolevulinic acid as a precursor of chlorophyll and 0-acetylserine as an S-acceptor to yield cysteine. In addition, about 900 other amino acids, which are not thought to be involved in primary metabolism, have been isolated from plants. These non-protein amino acids (NPAAs) are regarded as typical secondary metabolites with corresponding ecological functions. 

Beyond translation, proteins and peptides may be further modified by metabolic events within the cell. For instance, the hydroxyproline and hydroxylysine in collagen are formed from proltne and lysine that are hydroxyl-ated while they are part of the precursor protein molecule. A protein may also be post-translationally modified by cleavage of select bonds and/or by addition or subtraction of various kinds of groups. Insulin, for instance, is formed cleavage of a larger protnsultn molecule. Similar events occur in the activation of zymogens. 

Hydroxyproline is rapidly metabolized in a pathway initiated by the enzyme hydroxyproline oxidase (Chapter 17). 

All of the amino acids except lysine, threonine, proline, and hydroxyproline participate in transamination reactions. Transaminases exist for histidine, serine, phenylalanine, and methionine, but the major pathways of their metabolism do not involve transamination. Transamination of an amino group not at the a-position can also occur. Thus, transfer of 3-amino group of ornithine to a-ketoglutarate converts ornithine to glutamate-y-semialdehyde. 

Calcitonin is used in the treatment of Paget s disease (osteitis deformans), a chronic disorder characterized by increased bone remodeling, normocalcemia and normophosphatemia, frequent episodes of hypercalciuria leading to stone formation, and elevation of serum alkaline phosphatase and urinary hydroxyproline levels. The disease does not appear to be primarily a derangement of calcium metabolism. Calcitonin reduces the levels of serum alkaline phosphatase and urinary hydroxyproline, and may relieve other symptoms of the disease as well. Diphosphonates, especially etidronate disodium, also reduce bone resorption in this disease. Various cancers are accompanied by hypercalcemia and may respond to treatment with calcitonin. 

Most signs of scurvy can be related to inadequate or abnormal collagen synthesis. Ascorbate enhances prolyl and lysyl hydroxylase activities (Chapter 25). Collagen formed in scorbutic patents is low in hydroxyproline and poorly cross-linked, resulting in skin lesions, bone fractures, and rupture of capillaries and other blood vessels. The absolute amount of collagen made in scorbutic animals may also decrease independently of the hydroxylation defect. The anemia of scurvy may result from a defect in iron absorption or folate metabolism. 

Many of the chromatographic procedures are applicable to the measurement of labeled hydroxyproline in general they do not allow for multiple simultaneous determinations. Since collagen hydroxyproline is labeled only by administering its precursor, proline, in labeled form, the difficulties in radioactive studies have arisen largely because the nonhydroxy-proline metabolic products of proline or proline itself have not been rigorously separated from hydroxyproline or hydroxyproline-derived pyrrole. This is the purpose of the more recently introduced modifications for labeled hydroxyproline assay (Jll, L12). It is too early to know whether one or both of these will suffice for general use. 

In spite of these inherent shortcomings, the measurement of urinary hydroxyproline offers a useful index of bone matrix metabolism to add to the spate of techniques of bone mineral measurement used to study the endocrinology and metabolism of bone (B8). 

Although no determinations could be found, abnormal quantities of free hydroxyproline can be suspected in early infancy on the basis of the observed elevated free hydroxyproline levels in the urine and the presumptive mechanism of decreased metabolic breakdown and overflow... 

Thus, the major abnormalities of plasma free hydroxyproline appear to result from (1) the ingestion of hydroxyproline, collagen, or gelatin in any form, and (2) an inability to metabolize hydroxyproline from either prematurity or an inborn error of metabolism. Theoretically, a... 

Marked elevations of plasma peptide hydroxyproline have been observed by Dubovsky et al. in chronic renal failure (D7). The highest levels were seen when uremia and severe bone disease occurred together. Removal of the parathyroids in four patients (three primary and one secondary hyperparathyroidism) was associated with return to normal levels when renal function was normal, and significant reduction when renal failure was present. It seems possible that plasma peptide hydroxyproline might be a rapidly changing and sensitive indicator of bone metabolism which could be studied even with renal impairment, a major obstacle to most current techniques in the diagnosis of hyperparathyroid states. 

---