METABOLISM OF THE MUCOPOLYSACCHARIDES OF CONNECTIVE TISSUE
Authors: ALBERT DORFMAN
Journal: Pharmacological Reviews (1955)

An attempt has been made to bring together a variety of observations pertinent to the general subject of the metabolism of the mucopolysaccharides of connective tissue. This has necessitated the consideration of biochemical and biological phenomena which superficially, at least, appear unrelated. It is obvious that at this stage of knowledge no definitive picture can be drawn of either the mechanisms of synthesis or the influence of various biological factors thereon. There are, however, an increasing number of indications of directions for promising investigations aimed at the elucidation of the metabolism of these compounds, although many unsuspected surprises will undoubtedly appear.

In order to correlate some of the information which has been indicated in the text and to bring this information in relation to well established reactions of carbohydrate metabolism, the accompanying figures have been constructed.

Reactions which have been demonstrated are indicated by a solid arrow, postulated reactions by a dotted arrow, and reactions which, on the basis of available evidence, probably do not occur are indicated by cancelled arrows. Figure 1 is concerned with reactions of hexosamines. The schemes illustrated have been indicated on the basis of reactions which have been demonstrated in a variety of tissues. It is obviously impossible at this stage of development to speak of a pathway for any given tissue. For purposes of simplicity most of the chart is concerned only with glucosamine, although it is likely that similar pathways apply to galactosamine, but these have hardly been studied at all. Phosphorylation of galactosamine by galactokinase has been demonstrated. It is to be noted that N-acetylglucosamine is shown to be converted to unidine diphospho N-acetylglucosamine. The demonstration of the pyrophosphorolysis of UDPAG by an enzyme from liver nuclei, and the demonstration of the role of uridine compounds in the synthesis of other heterologous glycosides (sucrose, o-amino-phenol glucuronide) suggest the possible importance of this compound, although no direct evidence of the participation in mucopolysaccharide metabolism has yet been obtained. It should also be noted that UDPAG may arise by the amination and acetylation of UDPG.

Figure 2 illustrates some of the reactions involving the uronide portion of the molecule. Of importance to note is that, although α- and β-1-phosphoglucuronic acid have been made synthetically, there is, so far, no evidence of their participation in enzymatic reactions. It should again be emphasized that the predominance of evidence indicates that glucuronic acid per se does not enter into uronide synthesis. For these reasons it is suggested that oxidation of C6 may occur after glycoside formation.

In figure 3 an attempt is made to depict possible mechanisms involved in the metabolism of the entire polysaccharide molecule. The reactions given involve only H.A., it being assumed that similar reactions may be involved in the biosynthesis of C.S.A. which, of course, would, in addition, involve esterification of sulfate, the mechanism of which is entirely unknown.

The possible role of the uridine compounds in the biosynthesis of these heterologous polysaccharides is illustrated in only a very general way, since there are no data to point to probable mechanisms. It is obvious that this problem is complicated by the necessity of formation of different alternate bonds. In addition to the possible role of the uridine compounds, another mechanism is illustrated. This involves the formation of a glycoside of N-acetylglucosamine. Two reports have indicated that such glycosides may be formed by the action of hydrolytic enzymes (145, 159). A similar compound isolated by Meyer et al. (105) from cornea has been named keratosulfate. If mechanisms for the oxidation of the C6 carbon atom exist, such compounds might serve as intermediates in the synthesis of mucopolysaccharides, while without oxidation of the C6 carbon such compounds may play a role in the synthesis of other hexosamine containing compounds such as serum mucoproteins or blood group substances.

The schemes proposed in figures 1, 2, and 3 are not meant to lay definite claims to actual pathways, but to be used as a framework for the correlation of many scattered observations, and to point to certain suggestive pathways.

Kalckar and Strominger (personal communication) have recently isolated an enzyme from liver which brings about the oxidation of UDPG to UDPGA as postulated in this review.