Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution.
The surface of all mammalian cells is covered with a dense and complex array of sugar chains, which are frequently terminated by members of a family of molecules called sialic acids. One particular sialic acid called N-glycolylneuraminic acid (Neu5Gc) is widely expressed on most mammalian tissues, but is not easily detectable on human cells. In fact, it provokes an immune response in adult humans. The human deficiency of Neu5Gc is explained by an inactivating mutation in the gene encoding CMP-N-acetylneuraminic acid hydroxylase, the rate-limiting enzyme in generating Neu5Gc in cells of other mammals. This deficiency also results in an excess of the precursor sialic acid N-acetylneuraminic acid (Neu5Ac) in humans. This mutation appears universal to modern humans, occurred sometime after our last common ancestor with the great apes, and happens to be one of the first known human-great ape genetic differences with an obvious biochemical readout. While the original selection mechanisms and major biological consequences of this human-specific mutation remain uncertain, several interesting clues are currently being pursued. First, there is evidence that the human condition can explain differences in susceptibility or resistance to certain microbial pathogens. Second, the functions of some endogenous receptors for sialic acids in the immune system may be altered by this difference. Third, despite the lack of any obvious alternate pathway for synthesis, Neu5Gc has been reported in human tumors and possibly in human fetal tissues, and traces have even been detected in normal human tissues. One possible explanation is that this represents accumulation of Neu5Gc from dietary sources of animal origin. Finally, a markedly reduced expression of hydroxylase in the brains of other mammals raises the possibility that the human-specific mutation of this enzyme could have played a role in human brain evolution.
Varki
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Glycobiology Research and Training Center and Department of Medicine and University of California, San Diego, La Jolla, California 92093, USA.
D000818:Animals; D005075:Biological Evolution; D001921:Brain / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006031:Glycosylation; D015186:Hominidae / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007239:Infections / Q000378:metabolism; D008322:Mammals / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics; D009154:Mutation; D019158:N-Acetylneuraminic Acid / Q000378:metabolism / Q000502:physiology; D009438:Neuraminic Acids / Q000378:metabolism*
D009438:Neuraminic Acids; C032592:N-glycolylneuraminic acid; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase; D019158:N-Acetylneuraminic Acid