Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man

Abstract

1. The evidence is accumulating to suggest that glycine, the simplest amino acid, is conditionally essential in man. Benzoic acid, by conjugation with glycine to form hippuric acid, is known to deplete the free glycine pool of the body. Glycine is one substrate for the enzyme glutathione synthase (EC 6.3.2.3) and in the inborn error of metabolism in which glutathione synthase function is defective, increased quantities of 5-oxoproline are excreted in the urine.2. An oral dose of 4-10 g sodium benzoate was given to six normal adults to deplete the metabolic pool of glycine, and the urinary excretion of 5-oxoproline was followed for 6 h. In five of the six, a significant increase in the urinary 5-oxoproline was seen within 3 h.3. These-findings show that 5-oxoprolinuria can result from limited glycine availability, and may provide a useful test for assessing glycine sufficiency in a range of physiological and pathological states.In human nutrition, glycine has generally been considered to be a nutritionally dispensable (non-essential) amino acid (Rose, 1957). There is an absolute requirement for dietary glycine in the chick, apparently to satisfy the demands of uric acid synthesis (Almquist et al. 1940). Moreover, when the rat is faced with either the physiological stress of growth (Griffith, 1929), or the pathological stress of injury or trauma (Sitren & Fisher, 1977), there is a narrow margin between the metabolic demand for glycine and the rate at which glycine can be formed or made available in the body. A marginal state of glycine availability is probably more common than has been appreciated in the past (Jackson, 1983). Recently, we presented evidence to show that glycine might behave as a conditionally essential amino acid in the preterm human infant (Jackson et al. 1981 ; Catzeflis et al.1985). Furthermore, Yu et al. (1985) have shown that in normal adults on a low-protein diet, glycine production in the body is insufficient to satisfy the normal metabolic demand. These findings suggest that glycine insufficiency might occur far more frequently, and be far more widespread than had been recognized (Christensen, 1986). It was for this reason that we had been looking for an index of glycine sufficiency in humans, that would be relatively simple to use in a range of clinical situations. The measurement of 5-oxoproline (50P), L-pyroglutamic acid, in urine possibly represents just such an index. In a range of physiological and pathological conditions in which we had predicted an excessive demand for glycine, we were able to demonstrate increased urinary excretion of 50P (Jackson et al. 1986).50P is a normal intermediate of the y-glutamyl cycle (Meister, 1983) and may be detected at low levels in the urine of healthy individuals. Excessive loss of 5 0 P in the urine, 5-oxoprolinuria (SOPuria), may be found in inborn errors of metabolism associated with either an increased production (glutathione synthase (EC 6.3.2.3) deficiency) or decreased utilization (5-oxoprolinase deficiency) of 50P by the body (Meister, 1...

Urinary 5-L-oxoproline (pyroglutamic acid) excretion is greater in infants in Jamaica than in infants in England

“…We have associated a depletion of the metabolic pool of glycine with increased 5-L-oxoprolinuria in adults (Jackson et al, 1987;Jackson et al, 1996), and in infants gaining weight rapidly during recovery from severe malnutrition . On this basis we have used the excretion of 5-L-oxoproline as an index of the relative availability of glycine for metabolism, with increased excretion indicating a constraint on the endogenous biosynthesis of glycine relative to the satisfaction of the demands for metabolism (Jackson, 1991).…”

“…On this basis we have used the excretion of 5-L-oxoproline as an index of the relative availability of glycine for metabolism, with increased excretion indicating a constraint on the endogenous biosynthesis of glycine relative to the satisfaction of the demands for metabolism (Jackson, 1991). This would only apply when the availability of glycine is limiting for glutathione formation.…”

“…There are two pathways through which glycine is thought to be formed in the body, the glycine cleavage system and peroxisomal aminotransferase, and neither has been adequately characterized quantitatively (Jackson, 1991). Both pathways are dependent upon B vitamins as co-factors.…”

“…The urinary excretion of 5-L-oxoproline has been used as a marker for glycine status (Jackson, 1991). In normal adults low levels of 5-L-oxoproline are found in urine .…”

“…In normal adults low levels of 5-L-oxoproline are found in urine . The levels increase when the amount of glycine available to metabolism is reduced following the ingestion of large doses of compounds which conjugate with glycine, such as sodium benzoate or paracetamol (Jackson et al, 1987;Pitt, 1990), or on diets low in protein . During growth the demands for glycine increase and levels of urinary 5-L-oxoproline are higher in infancy (Jackson et al, 1997a), and particularly high in children gaining weight rapidly during recovery from severe malnutrition .…”