Importance Impacts Dietary Considerations

Introduction

One- carbon metabolism is a process of metabolism that makes a number of physiological processes possible, for instance biosynthesis, homeostasis in amino acids, redox defense and epigenetic maintenance. The activation and transfer of these one carbon units is mainly supported by folate co factors through folate metabolism. Unlike in plants, mammals, or rather animals in general need dietary folate. Insufficiency of folates in the body gives rise to a number of defects in the human functioning system, of course different in adults and infants (Copp et al., 2015). Folate metabolism also impacts epigenetics and cardiovascular health. One carbon metabolism is metabolism that involve one carbon units. The mobilization of carbon sources by eukaryotic cells supplies one carbon metabolism. Glycine, formate, serine, histidine and both dimethyl-glycine and sarcosine can plainly contribute to the THF bound one carbon pool. Quantitatively, the most important dietary sources of folate one- carbon units are choline, serine and flycine.

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Folate metabolism

A set of molecules that share a common structure is what makes up a folate. The common core structure usually consists of three chemical moieties. These folate molecules act as carriers that transport one carbon units. The process allows them to be assembled and manipulated so as to support metabolic processes. There are different products from the process dependent on the different carbon oxidation states; thymidine and Serine as products of 5, 10 Methylene- THF, Methionine as a product of 5-Methyl- THF, purines, formate and Carbon dioxide as products of 10- Formyl- THF (Krupenko et., 2010), among others. Additionally, one- carbon metabolism, through its transformations produces and consume redox equivalents. Many of these reactions are reversible, however, the oxidation of 10-formyl-THF to Carbon dioxide is not reversible. Recent reports have also depicted that the production of NADPH; through folate metabolism, is particularly important in mitochondrial redox homeostasis (Fan et al., 2014; Piskounova et al., 2015).

Many folate enzymes change the redox states of one- carbon units. When 5-1-methylene- THF is used as a substrate however, the Tetrahydrofolate itself alters in structure. A methyl unit is transferred by Thymidylate synthase to deoxyuridine monophostphate which abstracts from the Tetrahydrofolate itself the two electrons that are required to reduce one- carbon units, thus producing DHF as a product. The regeneration of THF is then dependent on the DHF produced. This activity involves a dihydrofolate reductase which is the canonical target of the anticancer and chemotherapeutic agent methotrexate. The same also applies in antibacterial trimethoprim. In both the mitochondria and the cytosol, complete set of enzymes link serine to formate. This ultimately allows for complete oxidative cycles, which catabolizes serine and synthesizes serine in the mitochondria and the cytosol respectively (Anderson et al., 2011).

In understanding, the division of folate metabolism in both the mitochondria and cytosol is encoded by variant isozymes and different folate chemical structures. Folate is fundamentally distributed by the circulation as a Tetrahydrofolate monoglutamate species (Wright et., 2007). These species are then actively transported through the cell membrane, with the aid of anionic reduced folate transporter (Hou and Matherly, 2014). In order to hold the folates in position within the cells, they have to be polyglumated. The polyglumation lowers their affinity for the transporter and also tend to enhance or heighten their affinity for folate enzymes. Cell proliferation is ultimately dependent on this activity, folate polyglumate synthetase (FPGS). The loss of this expression results in pemetrexed resistance. Certain mutations provide resistance to methotrexate in leukemic cells; those that impair RFC transport. Translocation of THF into the mitochondria is done by the mitochondrial folate transporter. Mutants who lack this helix protein are glycine auxotrophs, which is a common folate pathway loss phenotype (Chasin et al., 1995; Lowe et al., 1993).

Methotrexate and its effects

Plants, and most bacteria can synthesize their own folates, animals cannot. These folate molecules usually occur in polyglutamate form. This structure must be hydrolyzed to folate monoglutamates by the conjugase in brush border of the intestine. The monoglutamates are later absorbed in the duodenum and the upper intestine, then transported to the liver. It then becomes the principal form of the folate; 5-methyltetrahydrofolate. Generally, folates act as co- enzymes in the mediation of the one- carbon metabolism and they acquire and donate one- carbon units in their different forms of oxidation.

Because of such importance in other physiological processes, inhibition of folate metabolism hinders proliferation of cells; such is widely used as antibiotics and chemotherapeutics (Chattopadhyay et al., 2007). An example of such inhibitors is Methotrexate; methotrexate is an agent commonly used in chemotherapy and as a suppressant of the immune system. As a chemotherapeutic agent, methotrexate is used in the treatment of autoimmune conditions and diseases, ectopic pregnancy, medical abortions and ultimately cancer.

In chemical terms, methotrexate reduces the synthesis of tetrahydrofolate and as polyglutamate derivatives prevents dihydrofolate reductase and thymidylate synthase. As a result, the chemotherapeutic agent hinders the synthesis of RNA and DNA and fundamentally protein. The reason behind the use of this kind of substance in treatment of the afore mentioned diseases and conditions is that low- dose methotrexate inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase, onto which THF acts as a substrate in the synthesis of purine. As a consequence of this process, adenosine is released from cells (Derek et al., 2018). This adenosine acts of surface receptors of specific and individual cells so as to prevent their proliferation through suppression of the expression of adhesion molecules on both T- cells and neutrophils.

Health wise, the use of methotrexate may cause serious and grievous life threatening side effects. It may cause the reduction in the number of eukaryotic cells in the bone marrow, which as a result would cause a number of symptoms such as excessive tiredness, pale skin or difficulty in breathing. The use of methotrexate may also cause liver damage and lung damage. The risk of developing liver damage may also be higher dependent on the age and obesity.

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References

  • Anderson D and Stover J. (2009) SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis
  • Chasin L., Feldman A., Konstam M., and Urlaub G., (1974) Reversion of a Chinese hamster cell auxotrophic mutant
  • Chattopadhyay S., Moran G., and Goldman D., (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications, 404–417
  • Chen J., Chung F., Yang G., Gao H., Kasibhatla S., Laffitte B. (2013) Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth
  • Derek G (HONS), DM, MBBS (HONS)., Anthony P (2018) Medical Pharmacology and Therapeutics, 5th Ed
  • Fan J., Kamphorst J., Shlomi T., Thompson B., and Rabinowitz D. (2014) Quantitative flux analysis reveals folate-dependent NADPH production nature, 298–302
  • Hou Z., and Matherly L. (2014) Biology of the Major Facilitative Folate Transporters SLC19A1 and SLC46A1
  • Krupenko I., Dubard E., Strickland C., Moxley M., Oleinik V.,and Krupenko A. (2010) ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase.
  • Lowe E., Osborne B., Lin F., Kim S., Hsu C., and Shane B. (1993) Regulation of folate and one-carbon metabolism in mammalian cells. II. Effect of folylpoly-gamma-glutamate synthetase substrate specificity and level on folate metabolism and folylpoly-gamma-glutamate specificity of metabolic
  • cycles of one-carbon metabolism. J. Biol. Chem. 268
  • Piskounova E., Agathocleous M., Murphy M., Hu Z., Huddlestun E., Zhao Z., Leitch M., Johnson M., DeBerardinis J., and Morrison J. (2015) Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191
  • Wright J., Dainty R., and Finglas M. (2007) Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK
  • Copp J., Adzick S., Chitty S., Holmbeck N., and Shaw M. (2015) Spina bifida. Nat Rev Dis Primers 1

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