Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution

Varki, Ajit

doi:10.1002/ajpa.10018

Cited by 255 publications

(94 citation statements)

References 139 publications

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“…For example, the acquisition of genes encoding syncytins, proteins derived from the envelope protein of endogenous retroviral elements, enabled mammals to develop placenta and fetal-maternal tolerance and thereby fundamentally influenced the emergence of the entire Mammalia class [53,54]. Furthermore, loss of defensins could force our ancestors to develop alternative anti-viral strategies, some of which (such as inactivation of a gene responsible for synthesis of N-glycolylneuraminic acid, a common receptor for many pathogens) could beneficially affect brain development [55,56]. If the later scenarios are correct, than re-introduction of θ -defensins to the human population (either at the genetic or at the pharmaceutical levels) might bring all the benefits of increased resistance to viral and bacterial pathogens without negative side effects.…”

Section: Discussionmentioning

confidence: 99%

Retrocyclins neutralize bacterial toxins by potentiating their unfolding

Kudryashova

Seveau

et al. 2015

Biochemical Journal

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Defensins are a class of immune peptides with a broad range of activities against bacterial, fungal and viral pathogens. Besides exerting direct anti-microbial activity via dis-organization of bacterial membranes, defensins are also able to neutralize various unrelated bacterial toxins. Recently, we have demonstrated that in the case of human α- and β-defensins, this later ability is achieved through exploiting toxins’ marginal thermodynamic stability, i.e. defensins act as molecular anti-chaperones unfolding toxin molecules and exposing their hydrophobic regions and thus promoting toxin precipitation and inactivation [Kudryashova et al. (2014) Immunity 41, 709–721]. Retrocyclins (RCs) are humanized synthetic θ-defensin peptides that possess unique cyclic structure, differentiating them from α- and β-defensins. Importantly, RCs are more potent against some bacterial and viral pathogens and more stable than their linear counterparts. However, the mechanism of bacterial toxin inactivation by RCs is not known. In the present study, we demonstrate that RCs facilitate unfolding of bacterial toxins. Using differential scanning fluorimetry (DSF), limited proteolysis and collisional quenching of internal tryptophan fluorescence, we show that hydrophobic regions of toxins normally buried in the molecule interior become more exposed to solvents and accessible to proteolytic cleavage in the presence of RCs. The RC-induced unfolding of toxins led to their precipitation and abrogated activity. Toxin inactivation by RCs was strongly diminished under reducing conditions, but preserved at physiological salt and serum concentrations. Therefore, despite significant structural diversity, α-, β- and θ-defensins employ similar mechanisms of toxin inactivation, which may be shared by anti-microbial peptides from other families.

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Section: Discussionmentioning

confidence: 99%

Retrocyclins neutralize bacterial toxins by potentiating their unfolding

Kudryashova

Seveau

et al. 2015

Biochemical Journal

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“…The lack of this sugar is due to a mutation in the enzyme cytidine monophosphate-NeuAc hydroxylase that occurred in the hominid lineage subsequent to its divergence from the lineage of the great ape about 3 million y ago (53). There is evidence that the lack of production of NeuGc may be involved in resistance to infection by certain microbial pathogens, that immune system receptors that recognize sialic acid residues may be differentially modulated by NeuGc compared with NeuAc, and that dietary sources of NeuGc may lead to its accumulation and immune recognition in certain inflammatory conditions (53). Although there are no clear associations between the consumption of NeuGc and disease risk or incidence, it may be beneficial to reduce NeuGc-containing oligosaccharides in certain sensitive populations.…”

Section: Bmomentioning

confidence: 99%

Bovine Milk as a Source of Functional Oligosaccharides for Improving Human Health

Zivkovic

Barile

2011

Advances in Nutrition

145

120

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Human milk oligosaccharides are complex sugars that function as selective growth substrates for specific beneficial bacteria in the gastrointestinal system. Bovine milk is a potentially excellent source of commercially viable analogs of these unique molecules. However, bovine milk has a much lower concentration of these oligosaccharides than human milk, and the majority of the molecules are simpler in structure than those found in human milk. Specific structural characteristics of milk-derived oligosaccharides are crucial to their ability to selectively enrich beneficial bacteria while inhibiting or being less than ideal substrates for undesirable and pathogenic bacteria. Thus, if bovine milk products are to provide human milk-like benefits, it is important to identify specific dairy streams that can be processed commercially and cost-effectively and that can yield specific oligosaccharide compositions that will be beneficial as new food ingredients or supplements to improve human health. Whey streams have the potential to be commercially viable sources of complex oligosaccharides that have the structural resemblance and diversity of the bioactive oligosaccharides in human milk. With further refinements to dairy stream processing techniques and functional testing to identify streams that are particularly suitable for enriching beneficial intestinal bacteria, the future of oligosaccharides isolated from dairy streams as a food category with substantiated health claims is promising.

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“…In another example, the human-specific inactivation of the gene encoding the enzyme CMP- N -acetylneuraminic acid hydroxylase (CMAH) led to the deficiency of the mammalian common sialic acid Neu5Gc ( N -glycolylneuraminic acid) on the human cell surface [19]. This inactivation was due to an Alu-mediated sequence replacement [26] that occurred about 2.7 million years ago [27] and may have had several important consequences to human biology and evolution [28]. …”

Section: Introductionmentioning

confidence: 99%

Gene Losses during Human Origins

2006

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Pseudogenization is a widespread phenomenon in genome evolution, and it has been proposed to serve as an engine of evolutionary change, especially during human origins (the “less-is-more” hypothesis). However, there has been no comprehensive analysis of human-specific pseudogenes. Furthermore, it is unclear whether pseudogenization itself can be selectively favored and thus play an active role in human evolution. Here we conduct a comparative genomic analysis and a literature survey to identify 80 nonprocessed pseudogenes that were inactivated in the human lineage after its separation from the chimpanzee lineage. Many functions are involved among these genes, with chemoreception and immune response being outstandingly overrepresented, suggesting potential species-specific features in these aspects of human physiology. To explore the possibility of adaptive pseudogenization, we focus on CASPASE12, a cysteinyl aspartate proteinase participating in inflammatory and innate immune response to endotoxins. We provide population genetic evidence that the nearly complete fixation of a null allele at CASPASE12 has been driven by positive selection, probably because the null allele confers protection from severe sepsis. We estimate that the selective advantage of the null allele is about 0.9% and the pseudogenization started shortly before the out-of-Africa migration of modern humans. Interestingly, two other genes related to sepsis were also pseudogenized in humans, possibly by selection. These adaptive gene losses might have occurred because of changes in our environment or genetic background that altered the threat from or response to sepsis. The identification and analysis of human-specific pseudogenes open the door for understanding the roles of gene losses in human origins, and the demonstration that gene loss itself can be adaptive supports and extends the “less-is-more” hypothesis.

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Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution

Cited by 255 publications

References 139 publications

Retrocyclins neutralize bacterial toxins by potentiating their unfolding

Retrocyclins neutralize bacterial toxins by potentiating their unfolding

Bovine Milk as a Source of Functional Oligosaccharides for Improving Human Health

Gene Losses during Human Origins

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