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Metabolism of stored human and macaque RBC
RBC showing significantly higher levels of urate and hydroxyisourate (decreasing during storage).
Purine oxidation and salvage of deaminated purines involve using the amine group from aspartate through a reaction that generates fumarate, a minimally active path- way in mature RBC.35 Consistent with dysregulation of purine oxidation and salvage, species-specific changes in the levels of aspartate (higher in RM) and fumarate (higher in humans) were noted, suggesting a decreased rate of sal- vage reactions in RM RBC (Figure 5B). Similarly, RBC lev-
els of some carboxylic acids (e.g., malate, 2-hydroxyglu- tarate) were higher in humans, whereas others (e.g., cit- rate, a-ketoglutarate, succinate, oxaloacetate, itaconate) were higher in RM (Figure 5B), suggesting species-specific differences in transamination reactions (e.g., those depend- ent on the activity of alanine and aspartate aminotrans- ferases) or carboxylic acid metabolism via cytosolic iso- forms of Krebs cycle enzymes, all of which are active in mature RBC.34,36–38
In cells with mitochondria, carboxylate metabolism is
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Figure 1. Metabolomics of fresh red blood cells from healthy human volunteers and Rhesus macaques. (A) An overview of the experimental design. (B) Partial least square-discriminant analysis (PLS-DA) of red blood cells from 21 humans (red) or 20 Rhesus macaques (RM) (green). (C) An overview of the metabolites that were significantly different between the two groups (a vectorial version of the heat map is provided in Online Supplementary Figure S2). (D) A volcano plot highlighting the major pathways differing between humans (red) and RM (green). (E) Metabolite levels were correlated among each other (Spearman) in humans (red) and RM (green). (F) These correlations were used to map hierarchical clustering profiles in RM and humans. RM and human RBC showed significantly different metabolic correlation maps. Metabolites whose linear correlations differed significantly between species (>30% Δr between species, P<0.05) are highlighted in the rightmost panel in (F). (G) Some representative examples of correlations that are preserved (left) or lost (other panels) between species. PC: principal component; RBC: red blood cells; DPG: 2,3-diphosphoglycerate; HCA: hierarchical clustering analysis.
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