LC–MS/MS quantification of <i>N</i>-acetylneuraminic acid, <i>N</i>-glycolylneuraminic acid and ketodeoxynonulosonic acid levels in the urine and potential relationship with dietary sialic acid intake and disease in 3- to 5-year-old children

Chen, Yue; Pan, Lili; Liu, Geoffrey; Troy, Frederic A.; Wang, Bing

doi:10.1017/s0007114513002468

Cited by 40 publications

(30 citation statements)

References 37 publications

(70 reference statements)

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“…Several groups have independently reported nonsignificant levels (<2% of the sialic acid fraction) of Neu5Gc in the meat of different fish species belonging to the classes Actinopterygii (including tilapia, yellowfin tuna, mahi mahi, swordfish, rainbow trout and sardines, crucian carp, grass carp, golden pomphret, and European seabass) and Chondrichthyes (including the thresher shark) ( Chen et al 2014 ; Samraj et al 2015 ). The roe of salmon and whitefish, in contrast, exhibit high Neu5Gc concentrations ( Samraj et al 2015 ).…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc

Peri

Kulkarni

Feyertag

et al. 2017

Genome Biology and Evolution

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The enzyme CMP-N-acetylneuraminic acid hydroxylase (CMAH) is responsible for the synthesis of N-glycolylneuraminic acid (Neu5Gc), a sialic acid present on the cell surface proteins of most deuterostomes. The CMAH gene is thought to be present in most deuterostomes, but it has been inactivated in a number of lineages, including humans. The inability of humans to synthesize Neu5Gc has had several evolutionary and biomedical implications. Remarkably, Neu5Gc is a xenoantigen for humans, and consumption of Neu5Gc-containing foods, such as red meats, may promote inflammation, arthritis, and cancer. Likewise, xenotransplantation of organs producing Neu5Gc can result in inflammation and organ rejection. Therefore, knowing what animal species contain a functional CMAH gene, and are thus capable of endogenous Neu5Gc synthesis, has potentially far-reaching implications. In addition to humans, other lineages are known, or suspected, to have lost CMAH; however, to date reports of absent and pseudogenic CMAH genes are restricted to a handful of species. Here, we analyze all available genomic data for nondeuterostomes, and 322 deuterostome genomes, to ascertain the phylogenetic distribution of CMAH. Among nondeuterostomes, we found CMAH homologs in two green algae and a few prokaryotes. Within deuterostomes, putatively functional CMAH homologs are present in 184 of the studied genomes, and a total of 31 independent gene losses/pseudogenization events were inferred. Our work produces a list of animals inferred to be free from endogenous Neu5Gc based on the absence of CMAH homologs and are thus potential candidates for human consumption, xenotransplantation research, and model organisms for investigation of human diseases.

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Section: Resultsmentioning

confidence: 99%

Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc

Peri

Kulkarni

Feyertag

et al. 2017

Genome Biology and Evolution

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“…Given our hypothesis that tissue incorporation of Neu5Gc of dietary origin can have deleterious effects, it is important to determine the amounts present in typical components of the Western diet accurately. Although earlier studies attempted to quantify Neu5Gc distribution in food (23,(27)(28)(29), a systematic catalog of a wide variety of commonly consumed foods is lacking. Furthermore, based on recent studies (22), it appears that glycosidically bound Neu5Gc is the dietary source that is bioavailable for tissue incorporation, and not the free monosaccharide.…”

Section: Significancementioning

confidence: 99%

A red meat-derived glycan promotes inflammation and cancer progression

Samraj

Pearce

Läubli

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

339

328

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A well known, epidemiologically reproducible risk factor for human carcinomas is the long-term consumption of "red meat" of mammalian origin. Although multiple theories have attempted to explain this human-specific association, none have been conclusively proven. We used an improved method to survey common foods for free and glycosidically bound forms of the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc), showing that it is highly and selectively enriched in red meat. The bound form of Neu5Gc is bioavailable, undergoing metabolic incorporation into human tissues, despite being a foreign antigen. Interactions of this antigen with circulating anti-Neu5Gc antibodies could potentially incite inflammation. Indeed, when human-like Neu5Gc-deficient mice were fed bioavailable Neu5Gc and challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Such mice are already prone to develop occasional tumors of the liver, an organ that can incorporate dietary Neu5Gc. Neu5Gc-deficient mice immunized against Neu5Gc and fed bioavailable Neu5Gc developed a much higher incidence of hepatocellular carcinomas, with evidence of Neu5Gc accumulation. Taken together, our data provide an unusual mechanistic explanation for the epidemiological association between red meat consumption and carcinoma risk. This mechanism might also contribute to other chronic inflammatory processes epidemiologically associated with red meat consumption.

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“…Dietary sources that are rich in Neu5Gc include red meats such as beef, pork, lamb, and to a much lesser degree, cow’s milk products. Of significant note is the fact that plants and poultry do not contain Neu5Gc, and that fish samples studied so far contain low to trace amounts (58, 60). …”

Section: Neu5gc Can Be Metabolically Incorporated Into Human Tissues mentioning

confidence: 99%

Involvement of a Non-Human Sialic Acid in Human Cancer

et al. 2014

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Sialic acids are common monosaccharides that are widely expressed as outer terminal units on all vertebrate cell surfaces, and play fundamental roles in cell–cell and cell–microenvironment interactions. The predominant sialic acids on most mammalian cells are N-glycolylneuraminic acid (Neu5Gc) and N-acetylneuraminic acid (Neu5Ac). Neu5Gc is notable for its deficiency in humans due to a species-specific and species-universal inactivating deletion in the CMAH gene encoding the hydroxylase that converts CMP-Neu5Ac to CMP-Neu5Gc. However, Neu5Gc is metabolically incorporated into human tissues from dietary sources (particularly red meat), and detected at even higher levels in some human cancers. Early life exposure to Neu5Gc-containing foods in the presence of certain commensal bacteria that incorporate dietary Neu5Gc into lipooligosaccharides can lead to generation of antibodies that are also cross-reactive against Neu5Gc-containing glycans in human tissues (“xeno-autoantigens”). Such anti-Neu5Gc “xeno-autoantibodies” are found in all humans, although ranging widely in levels among individuals, and displaying diverse and variable specificities for the underlying glycan. Experimental evidence in a human-like Neu5Gc-deficient Cmah−/−mouse model shows that inflammation due to “xenosialitis” caused by this antigen–antibody interaction can promote tumor progression, suggesting a likely mechanism for the well-known epidemiological link between red meat consumption and carcinoma risk. In this review, we discuss the history of this field, mechanisms of Neu5Gc incorporation into tissues, the origin and specificities of human anti-Neu5Gc antibodies, their use as possible cancer biomarkers, implications of xenosialitis in cancer initiation and progression, and current and future approaches toward immunotherapy that could take advantage of this unusual human-specific phenomenon.

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LC–MS/MS quantification of N-acetylneuraminic acid, N-glycolylneuraminic acid and ketodeoxynonulosonic acid levels in the urine and potential relationship with dietary sialic acid intake and disease in 3- to 5-year-old children

Cited by 40 publications

References 37 publications

Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc

Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc

A red meat-derived glycan promotes inflammation and cancer progression

Involvement of a Non-Human Sialic Acid in Human Cancer

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