Evidence that oxidative stress contributes to the clinical and pathophysiologic manifestations of the edematous syndromes of childhood PEM is based on higher plasma concentrations of biomarkers of tissue oxidant damage and lower blood concentrations of the ubiquitous antioxidant/detoxicant GSH. We have demonstrated that deficiency of cysteine (csy), a GSH precursor, is responsible for slower GSH synthesis. The cause of inadequate cysteine supply in edematous, but not in non-edematous PEM, is not known. To determine the cause of this cysteine deficiency in edematous PEM the following hypotheses will be tested: 1) In edematous but not in nonedematous PEM, a marked suppression of protein breakdown rate results in reduced methionine availability for cysteine synthesis. A corollary to this hypothesis is that methionine supplementation permits adequate cysteine synthesis and hence, faster nonnalization of GSH synthesis thereby reducing oxidant damage. 2) Alternatively, because GSH is a regulator of SAMe synthetase, decreased GSH availability impairs conversion of methionine to SAMe, and hence to cysteine via the transmethylation-transsulfuration pathway. A corollary to this hypothesis is that nutritional rehabilitation with cysteine supplementation or a cysteine-rich whey based formula will permit faster normalization of GSH synthesis and availability thereby restoring methionine metabolism to SAMe and hence to cysteine. Using biochemical, immunological and stable isotope tracer methods, these hypotheses will be tested in 6-18 mo. old infants with PEM. Experimental protocol 1 will determine differences in children with edematous versus non-edematous PEM in 1) methionine flux and its release from proteolysis, its conversion to homocysteine (rate of transmethylation) and conversion of homoeysteine to methionine (rate of remethylation) and to cysteine (rate of transsulfuration) :!) total, protein-derived and methionine-derived cysteine fluxes, homocysteine and SAMe concentrations. Experimental protocols 2 and 3 will compare in children with edematous PEM the effect of feeding a) a methionine versus alanine supplemented diet and b) a cysteine versus alanine supplemented diet versus a cysteine-rich whey based diet on the same kinetic parameters outlined in I & 2 plus the synthesis of erythrocyte GSH, plasma concentrations of indicators of oxidant damage, immune function, protein synthesis, body composition and time taken to lose edema, liver fat, and to restore appetite. The data obtained will provide insight into the role of methionine availability and its metabolism in the cysteine deficiency, hence the GSH deficiency of edematous PEM and whether therapeutic approaches aimed to replenish methioninc and cysteine supply will accelerate clinical and metabolic recovery in children with the edematous PEM syndromes.
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