One Carbon Unit Metabolism Lecture Notes PDF

One Carbon Unit Metabolism Prepared By Dr. Walaa Ibrahim & Dr. Reem Sallam Medical Biochemistry & Molecular Biology gu.edu.eg  Intended learning outcomes of the lecture: By the end of this lecture, you would be able to...

One Carbon Unit Metabolism Prepared By Dr. Walaa Ibrahim & Dr. Reem Sallam Medical Biochemistry & Molecular Biology gu.edu.eg  Intended learning outcomes of the lecture: By the end of this lecture, you would be able to: - 1. Identify forms of one carbon units. 2. Identify the carriers of one carbon units. 3. Describe the sources and fate of each unit. 4. Explain the biomedical importance of Folic Acid analogues. 5. Enumerate the clinical manifestations of folate deficiency. Overview Some synthetic pathways require the addition of single carbon groups These single carbon groups can be transferred from carrier compounds such as THF and SAM to specific structures that are being synthesized The “one-carbon pool” refers to the single carbon units attached to this group of carriers Types of one carbon units Methyl group (-CH3) Methylene group (-CH2-) Methenyl group (-CH=) Formyl group (-CH=O) Formimino group (-CH=NH) CO2 group One carbon unit can be carried & transferred by: 3-S- adenosyl 1-Biotin 2-Tetrahydrofolate methionine Carries CO2 -CH3, CH2, CH3 CH=, CHO, CHN,  1- Biotin CO2,is carried by the vitamin biotin, which is required for carboxylation reactions but is not considered a member of the one-carbon pool. Example of a Carboxylation reaction 2- Tetrahydrofolate(THF) The biologically active form of folic acid is tetrahydrofolate (THF), which is produced by the two-step reduction of folate by dihydrofolate reductase (DHFR) (NADPH- dependent enzyme). Folic acid is reduced to dihydrofolate then to tetrahydrofolate by the same enzyme A key feature of THF is that it can carry a variety of 1-carbon groups. One-carbon groups transferred by THF are attached either to N 5 or N10, or they form a bridge between N 5 and N10. The collection of one-carbon groups attached to THF is known as the one- carbon pool No need to memorize structures!)  Metabolism of one carbon atom groups Important to know these amino acids Amino Acids: Tryptophan Sources of one carbon unit Products (Fates) of one carbon unit I- Sources of one-carbon units: Only the names of the amino acids are needed 1- α-carbon of glycine 2- β-carbon of serine: the major carbon source of one-carbon groups in the human. 3- Tryptophan forms formyl kynurenine that produces formyl THF 4- Histidine forms formimino glutamate that produces formimino THF  Example of Sources of one- No need to carbon units: b-carbon of serine memorize structures!) PLP Ser Hydroxymethyl Transferase FH4 (N5, N10)-CH2 FH4 This is THF carrying one carbon unit Serine is the major carbon source of one-carbon groups in the human. The reaction is catalyzed by the enzyme serine hydroxymethyl transferase. PLP is a coenzyme for this reaction This reaction produces glycine and N 5,N10-methylene-FH4. Examples of Fates of one-carbon units 2- Synthesis of 1- Synthesis of methionine from serine from glycine homocysteine by CH3-THF 4- Synthesis of 3- Synthesis of dTMP from dUMP purine nucleotide using Methylene group (-CH2)  Examples of Fates of one-carbon units Synthesis of methionine from homocysteine by CH3-THF Methionine Homocystiene  Examples of Fates of one-carbon units, continue…. Synthesis of purine nucleotide The Formyl group carried by tetra hydrofolate (THF) is the source of carbon 2 and 8 in purine nucleotides C2 & C8 of purines by formyl THF It is important for DNA synthesis (replication) especially in rapidly dividing cells e.g., developing RBCs in bone marrow, hair follicle cells, surface epithelial cells of mouth, GIT, urinary tract, and respiratory tract.  Examples of Fates of one-carbon units, continue…. The nucleotide (dTMP) Synthesis of dTMP from dUMP: is produced from (dUMP) by a reaction in which dUMP is methylated to form dTMP The source of carbon is (N5,N10-methylene- THF). dUMP Two hydrogen atoms from THF are used in the reaction. Consequently, dihydrofolate (DHF) is produced. Reduction of dihydrofolate (DHF) catalyzed by dihydrofolate reductase (DHFR) to regenerates THF. Tetrahydrofolate (THF) is required for the synthesis of deoxythymidine monophosphate (dTMP) and the Purine bases used to produce the precursors for DNA replication. Therefore, THF is required for cell division Blockage of the synthesis of thymine and the purine bases, either by a dietary deficiency of folate or by drugs that interfere with folate metabolism (e.g. Methotrexate), results in a decreased rate of cell division and growth.  Folate analogues Methotrexate Sulfonamide Ø Potent inhibitor of human Ø It inhibits synthesis of folic dihydrofolate reductase acid only in bacteria (DHFR); so, it prevents folate Ø Sulfa drugs do not affect human activation to THF. DNA or RNA synthesis because mammalian cells can not synthesize folic acid. Methotrexate is anti-cancer drug. It is used as antibiotic  Clinical manifestation of folate deficiency Megaloblastic anemia Glossitis and gastrointestinal Neural tube defects (NTD: Spina (macrocytic disturbances bifida and anencephaly) in the fetus hyperchromic anemia) Ø Due to impaired DNA Ø NTDs occur in the first synthesis in GIT mucosal lining. week’s pregnancy. Ø Folic acid supplementation during the first trimester significantly reduces the defects Practice Question In neural tube defect, which of the following is (are) the one-carbon unit(s) that can be carried by the active form of the vitamin whose deficiency results in this clinical manifestation? A- Carbon dioxide (CO2) B- Aldehyde group C- Carbon dioxide (CO2) and methyl (CH3) D- Methyl, methylene, methenyl, Formyl, formimino E- Methionine, homocysteine, Serine, Glycine, Histidine Answer to Practice Question In neural tube defect, which of the following is (are) the one-carbon unit(s) that can be carried by the active form of the vitamin whose deficiency results in this clinical manifestation? A- only CO2 B- Aldehyde group C- Carbon dioxide (CO2) and methyl (CH3) D- Methyl, methylene, methenyl, Formyl, formimino E- Methionine, homocysteine, Serine, Glycine, Histidine Practice Question Which of the following is the mechanism of action of methotrexate as anti-cancer drug? A- Inhibition of folic acid synthesis in rapidly dividing cells B- Inhibition of dihydrofolate reductase enzyme C- Stimulation of serine hydroxy methyl transferase D- Inhibition of Glycine cleavage system E- Activation of transmethylation reaction Answer to Practice Question Which of the following is the mechanism of action of methotrexate as anti-cancer drug? A- Inhibition of folic acid synthesis in rapidly dividing cells B- Inhibition of dihydrofolate reductase enzyme C- Stimulation of serine hydroxy methyl transferase D- Inhibition of Glycine cleavage system E- Activation of transmethylation reaction Practice Question Which one of the following is the source of carbon 2 and 8 in purine nucleotides? A- CO2 carried by biotin B- Methyl group (CH3) carried by SAM C- Formyl group carried by tetra hydrofolate (H4F) D- Formimino group carried by SAM E- Methylene group carried by tetra hydrofolate (H4F) Answer to Practice Question Which one of the following is the source of carbon 2 and 8 in purine nucleotides? A- CO2 carried by biotin B- Methyl group (CH3) carried by SAM C- Formyl group carried by tetra hydrofolate (THF) D- Formimino group carried by SAM E- Methylene group carried by tetra hydrofolate (H4F) Thank You gu.edu.eg