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Micronutrients
Published in Chuong Pham-Huy, Bruno Pham Huy, Food and Lifestyle in Health and Disease, 2022
Chuong Pham-Huy, Bruno Pham Huy
Adenosyl and methylcobalamin coenzymes are derived from cobalamin or vitamin B12 and assist in the conversion of homocysteine to the amino acid methionine. They also participate in the oxidation of amino acids and odd-chain fatty acids, and the removal of a methyl group from methyl folate, which regenerates tetrahydrofolate (90–91). Tetrahydrofolate serves as a key coenzyme in the biosynthesis of purines and pyrimidines.
Respiratory, endocrine, cardiac, and renal topics
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Following intrathecal administration, concentrations known to be cytotoxic in vitro against leukaemia blast cells can be achieved in the CSF. However, the drug distribution within the upper cerebral spaces varies strongly from one patient to the other. That is why neuromeningeal prophylaxis calls for the administration of high doses of methotrexate (> 1.5 g/m2). After intrathecal injection, methotrexate diffuses into systemic circulation and can induce systemic toxicity, in particular in case of repeated intrathecal injections. Polymorphism of the 5,10 methylene tetrahydrofolate gene may be associated with a higher toxicity risk.
Nutritional Deficiencies
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Deepa Bhupali, Fernando D. Testai
Dietary methionine is metabolized to S-adenosylmethionine, which is necessary for the methylation of myelin sheath products. Downstream, S-adenosylmethionine is converted to homocysteine, and this may enter the remethylation or the transsulfuration pathway. In the remethylation pathway, the methionine synthase, which requires methylcobalamin as a cofactor, catalyzes the reaction of homocysteine and methyltetrahydrofolate to produce methionine and tetrahydrofolate. Tetrahydrofolate is the precursor required for purine and pyrimidine synthesis (Figure 10.9). Adenosylcobalamin is necessary for the conversion of l-methylmalonyl-CoA to succinyl-CoA in the mitochondria (Figure 17.1).
Fooled by the fragments: vitamin B12 deficiency masquerading as thrombotic thrombocytopenic purpura
Published in Journal of Community Hospital Internal Medicine Perspectives, 2021
Pegah Jahangiri, Rachel Hicks, Prabjot K. Batth, Christopher J. Haas
Vitamin B12 is a water-soluble vitamin with an essential role in DNA synthesis, hematopoiesis, and myelination. Vitamin B12 is a necessary cofactor for the conversion of methylmalonyl coenzyme A to succinyl coenzyme A via methylmalonyl coenzyme A mutase (Figure 2), enabling the breakdown of odd-chained fatty acids and some amino acids. It is also a required cofactor for methionine synthase, which catalyzes the conversion of homocysteine to methionine, ultimately allowing for the generation of tetrahydrofolate, a biologically active form of folate needed in DNA synthesis (Figure 2). Insufficient levels of vitamin B12 lead to reduced function of methylmalonyl coenzyme A mutase and methionine synthase, with a resultant accumulation of the precursors methylmalonyl coenzyme A and homocysteine, respectively. Classically, vitamin B12 deficiency manifests as a macrocytic, megaloblastic anemia and in severe cases, subacute combined degeneration of the posterior columns of the spinal cord. In rare cases, severe vitamin B12 deficiency can present as a pseudo-microangiopathic hemolytic anemia/TTP, characterized by thrombocytopenia and hemolytic anemia (i.e., elevated LDH, low haptoglobin, hyperbilirubinemia, and schistocytes). In contrast to classic microangiopathic hemolytic anemia/TTP, vitamin B12-related pseudo-TTP presents as a macrocytic, megaloblastic anemia with reticulocyte hypoproliferation, elevated levels of homocysteine and MMA, and a low vitamin B12. Management of this masked deficiency requires only vitamin B12 supplementation in contrast to initiation of plasmapheresis required for true TTP.
Development of new agents for peripheral T-cell lymphoma
Published in Expert Opinion on Biological Therapy, 2019
Yuta Ito, Shinichi Makita, Kensei Tobinai
Pralatrexate (10-propargyl-10-deazaaminopterin) is an anti-folate agent that inhibits dihydrofolate reductase (DHFR). As DHFR is a key enzyme in the conversion of dihydrofolate to tetrahydrofolate, which is required for the synthesis of thymidylate and purine nucleotides, the inhibition of DHFR blocks cell division in the S phase [7]. Compared with other anti-folate agents, such as methotrexate, high intracellular concentrations of pralatrexate can be reached owing to its high affinity for the reduced folate carrier-1 (RFC-1) that takes pralatrexate into intracellular space. This higher affinity for RFC-1 may be associated with the greater selectivity of pralatrexate for tumor cells because many tumors overexpress RFC-1. Furthermore, intracellular pralatrexate is metabolized into a polyglutamated form by folylpolyglutamate synthetase; polyglutamates are preferentially retained in the intracellular space, which makes them less susceptible to efflux-based drug resistance [8].
The relationship between gene polymorphism of MTRR A66G and lower extremity deep venous thrombosis
Published in Hematology, 2018
Tetrahydrofolate in the body can be combined with a carbon unit at the 5-N and 10-N positions into tetrahydrofolic acid. Methyltetrahydrofolic acid was synthesized by MTHFR [30]. Under the catalysis of MS, homocysteine reacts with 5-methyltetrahydrofolic acid, which is demethylated into tetrahydrofolate, and homocysteine is methylated into methionine, to complete a cycle of tetrahydrofolate. Under the action of cystathionine-β-synthase (CBS), with vitamin B6 as a cofactor, homocysteine and silk amino acids combined to form cystathionine, further forming cysteine [31]. MTRR is a cofactor for MS and catalyzes the regeneration of methylcobalamin. MTRR maintains the MS in a reduced state while maintaining its methylation status by reducing vitamin B6. Studies have shown that the polymorphism of 66 A-G loci in MTRR caused methionine to be replaced by isoleucine [32]. The decrease in enzyme activity leads to hyperhomocysteinemia due to the abnormal metabolism of folic acid, which can cause vascular endothelial damage and dysfunction and stimulate the proliferation of vascular smooth muscle cell, leading to the imbalance between vascular relaxing factor and vascular contraction factor eventually, thus DVT occurs.