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Arginine synthesis is a complex, age-dependant process involving multiple precursors and enzymes, and the interorgan transfer of substrates. The objectives of this thesis were to elucidate arginine synthesis from enteral precursors in newborn infants and in healthy adults using stable isotope methodology. In the first, of four studies, I validated the use of a non-invasive methodology using urinary amino acids for stable isotope studies of arginine synthesis and demonstrated a known, but under-recognised, problem with D-amino acid contamination of tracers. Implementing chiral chromatography, this issue was further investigated using samples from previous studies in our laboratory with several different isotopes. I demonstrated the novel finding that the impact of D-amino acids is dependent on the tracer used, and also on the age of the subject. In the second study, I used a multi-tracer design to assess arginine synthesis from enteral proline or glutamate in healthy preterm infants. Labeled arginine (M+2), proline (M+1) and glutamate (M+3) were given enterally to fifteen stable, growing preterm infants (gestational age at birth 30-35 weeks) at 1-3 weeks’ postnatal age. I found only arginine synthesis from proline, with no synthesis from glutamate. I conclude that enteral proline is the major contributor to arginine synthesis in vivo in human preterm infants. In the third study, I measured arginine synthesis from enteral proline in adults. I have demonstrated that enteral proline contributes significantly, ~25%, to newly synthesised arginine. In the fourth study, I used two glutamine tracers, 1-13C and 2-15N, to determine if glutamine is a carbon or nitrogen donor for arginine. I showed that enteral glutamine contributes ~50% of the carbon skeleton for arginine and that the 2-15N tracer significantly overestimates arginine synthesis, with the labeled N being transferred through transamination from pyrroline-5-carboxylate (to ornithine, rather than directly from glutamate to pyrroline-5-carboxylate. In conclusion, proline is the sole precursor for arginine in human neonates and combines with glutamaine as the dietary precusor in adults. As a precussor for arginine, though, glutamine’s main role is in provision of nitrogen independent of the carbon skeleton.

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BACKGROUND: The protein tyrosine phosphatase non receptor type 22 (PTPN22) gene inhibits T-cell activation. A functional single nucleotide polymorphism (SNP) Arg620Trp (rs2476601), resulting from a C→T substitution at nucleotide position 1858, is a significant risk factor for rheumatoid arthritis (RA) in European populations. The variant allele results in a gain of function that alters the threshold for T-cell signalling and abnormal T regulatory cell function. AIM: To investigate the role of the PTPN22 R620W polymorphism in disease susceptibility and severity in Black South Africans (BSA) with RA. METHODS: A cohort of 187 BSA patients with RA and 93 ethnically matched Black and 60 White controls with no history of RA or other autoimmune diseases were studied. Genotyping was performed by the polymerase chain reaction and pyrosequencing. RESULTS: The rs2476601 SNP was nonpolymorphic in both Black patients and Black control subjects with total absence of the variant ‘T’ allele. In White control subjects the frequency of the ‘T’ allele was 0.092, with T/T, C/T and C/C genotype frequencies of 0.00, 0.183, and 0.817, respectively. CONCLUSION: This study shows that the rs2476601 SNP of the PTPN22 gene is nonpolymorphic in BSA and therefore not associated with RA but the minor ‘T’ allele frequency in White South Africans is similar to that in other European populations. However, since variations in the rest of the gene were not investigated, these results do not exclude other PTPN22 polymorphisms from playing a role in RA susceptibility in BSA.