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Arginine metabolic pathways and their deviations in AD brain. Arginine is primary substrate metabolized by nitric oxide synthases (NOS1 and NOS3 under physiological conditions), arginase 1 (Arg1) and arginine decarboxylase (ADC). Arginase 2 (Arg2) plays a role in extra-urea cycle arginine metabolism. Arginine is cleaved by arginase to form urea and ornithine at the final step of the urea cycle. The urea cycle consists of N-acetylglutamate synthase (NAGS), which is an allosteric cofactor for catalytic enzyme carbamoyl phosphate synthase (CPS1), and other four catalytic enzymes: ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (Arg1). NAGS, CPS1 and OTC are localized in the mitochondria, while ASS1, ASL, and ARG1 are in the cytosol. Two enzymes: OTC and CPS1 are present in very low concentrations in the human brain. As a result, the brain urea cycle is not efficient and to remove ammonia and relies on alternative glutamine synthesis by glutamine synthetase (GS). Glutamine concentration rises in AD brain. Glutamate dehydrogenase (GDH) catalyzes the deamination of glutamate to α-ketoglutarate (α-KG), which concentrations also increase in AD brain, and ammonia (NH3). The mitochondrial ornithine transporter (1), citrin (2), and the mitochondrial cationic amino acid transporter type 1 (3). Red arrows indicate elevated levels; blue arrows designate reduced ones. The intensity of the circles’ color reflects the level of activation (arbitrary scale). Argininosuccinate lyase (ASL), argininosuccinate synthetase (ASS), nitric oxide (NO), ornithine decarboxylase (ODC), spermidine synthase (SPDS), spermine synthase (SPMS), agmatinase (AGM), ornithine aminotransferase (OAT).

Metabolites are presented in abbreviated form within rectangles. Enzymes and transporters are circles. Kinetic data is available for those shaded grey. Met = methionine; Arg = arginine; Gly = glycine; Glu = glutamate; Cys = cysteine; ATP = adenosine triphosphate; SAM = S-adenosylmethionine; dcSAM = decarboxylated S-adenosylmethionine; MTA = methylthioadenosine; Orn = ornithine; Put = putrescine; Spd = spermidine; c-GC = c-glutamylcysteine; GSH = glutathione; GSpd = glutathionylspermidine; T(SH₂) = reduced trypanothione; TS₂ = oxidised trypanothione; NADP = nicotinamide adenine dinucleotide phosphate; NADPH = reduced nicotinamide adenine dinucleotide phosphate; Glc = glucose; G6P = glucose 6-phosphate; Ru5P = ribulose 5-phosphate; Ox = oxidised cellular metabolites; Red = reduced cellular metabolites. 1. = methionine transport; 2. = arginine transport; 3. = glycine transport; 4. = glutamate transport; 5. = cysteine transport; 6. = methionine adenosyltransferase; 7. = arginase (N.B., a robust arginase gene orthologue has not been annotated in the T. brucei genome project, raising the possibility that arginine does not serve as a source of ornithine in these cells); 8. = S-adenosylmethionine decarboxylase; 9. = prozyme; 10. = ornithine decarboxylase; 11. = spermidine synthase; 12. = c-glutamylcysteine synthetase; 13. = glutathione synthetase; 14. = c-glutathionylspermidine synthetase; 15. = trypanothione synthetase/amidase (in T. brucei 14. & 15. are catalysed by a single protein); 16. = trypanothione reductase; 17. oxidative pentose phosphate pathway (glucose 6-phosphate dehydrogenase, 6-phopshogluconolactonase & 6-phosphoglconate dehydrogenase); 18. = glucose transporter; 19. = hexokinase (this enzyme links the redox pathway to glycolysis); 20. = pyruvate transporter; 21. = methionine cycle enzymes; 22. The pathway of electrons from reduced trypanothione for final acceptance on oxidised cellular metabolites or macromolecules is complex, involving transfers via other redox active intermediates including tryparedoxin (thioredoxin-like proteins) and peroxidoxin.