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Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
Folic acid (B9)
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Folic acid (B9)

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Metabolism of Folic Acid (B9)

Metabolism of Folic Acid (B9)

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  • 1. FOLIC ACID (B9] Gandham. Rajeev Department of Biochemistry, Akash Institute of Medical Sciences & Research Centre, Devanahalli, Bangalore, Karnataka, India. E-Mail: gandhamrajeev33@gmail.com
  • 2.  The word folic acid is derived from latin word Folium means leaf & it is also isolated from the leafy vegetable spinach  Folic acid mainly consists of three components  Pteridine ring  PABA (p-amino benzoic acid)  Glutamic acid residue (1 to 7 residues)  Hence it is known as Pteroyl-glutamic acid
  • 3.  Tetrahydrofolate (THF or FH4) is the active form of folic acid 5 10
  • 4. N H H HN I H H2N N N H I N - CH2 – NH- O II - C H I - N - CH –COO- I CH2 I CH2 I COO- 8 7 6 5 Folic Acid Dihydrofolate reductase 2NADPH + 2H+ 2NADP 5,6,7,8 – Tetrahydrofolic acid (THF)
  • 5.  Absorption:  Formation of monoglutamate form:  Most of the dietary folic acid exists as polyglutamate with 3-7 glutamate residues  It is not absorbed in the intestine  The glutamate side chains are cleaved by the enzyme folate conjugase or polylpolyglutamate hydrolase
  • 6.  Only monoglutamyl form of folic acid is absorbed from the intestine  The enzyme folate conjugase is present in duodenum & jejunum  Mucosal uptake & metabolism in mucosal cell  Folate monoglutamate is taken up by the mucosal cell  In the mucosal cell, folate monoglutamate is reduced to tetrahydrofolate & methylated to form N5 methyl tetrahydrofolate (in circulation)
  • 7.  N5 methyl tetrahydrofolate enters the circulation  Storage:  Inside the cells, tetrahydrofolates are found as polyglumates (with 5-6 amino acid residues)  Which are biologically most potent  Polyglutamate is the storage form of folic acid  It is mainly stored in the liver (10-20 mg)
  • 8.  Folic acid is not biologically active  The active coenzyme forms of folic acid are  Tetrahydrofolic acid (FH4)  N5 methyl tetrahydrofolic acid (N5FH4)  N5,N10 methylene tetrahydrofolic acid  N10 formyl tetrahydrofolate(N10 formyl FH4)  N5 formimino tetrahydrofolate (N5 formimino FH4)
  • 9.  N5 formyl tetrahydrofolate (N5 formyl FH4)  N5,10 methenyl tetrahydrofolate N5,10 methenyl FH4)  N5 formyl THF -CHO  N10 formyl THF -CHO  N5 formimino THF -CH=NH  N5,N10 methenyl THF= CH  N5,N10 methylene THF =CH2  N5 methyl THF - CH3
  • 10.  The coenzymes of folic acid are actively involved in the one carbon metabolism  THF acts as an acceptor or donor of one carbon units (formyl, methyl etc.) in reactions involving amino acid & nucleotide metabolism  The one carbon units bind with THF at position N5 or N10 or on both N5 &N10 of pteroyl structure
  • 11.  Amino acid metabolism is important for transfer or exchange of one carbon units  The following one carbon fragments are involved in biological reactions  Methyl (-CH3)  Hydroxymethyl (-CH2OH)  Methylene (=CH2)  Methenyl (-CH=)  Formyl (-CH=O)  Formimino (-CH=NH)
  • 12.  THF is a versatile coenzyme actively participates in one carbon metabolism  Transfer of methyl groups from S- adenosylmethionine  B12 is also involved  The one carbon units covalently binds with THF at position N5 or N10 or on both N5 &N10 of pteroyl structure of folate
  • 13.  Many compounds particularly amino acids act as donors of one carbon units  The formate is released from glycine & tryptophan metabolism combines with THF to form N10 – formyl THF  Histidine contributes formimino fragment to produce N5 – formimino THF  Serine is converted to glycine, N5,N10 methylene THF is formed  This is most common entry of 1C units into one carbon pool
  • 14.  Choline contributes to the formation of N5 methyl THF  Different derivatives of THF carrying one carbon units are interconvertible, & this is metabolically significant for the continuity of one carbon pool Utilization of one carbon units  Utilized for synthesis of wide variety of compounds
  • 15.  These includes  Purines  Formylmithionine tRNA (initiation of protein synthesis)  Glycine  Pyrimidine nucleotide etc Role of methionine & vitamin B12  Methyl group is an important one carbon unit  Methionine is active donor of methyl groups in transmethylation reactions
  • 16.  After the release of methyl group, methionine is converted to homocysteine  For regeneration of methionine, homocysteine & N5-methyl THF are required & this reaction is dependent on Vitamin B12  The one carbon pool, under the control of THF, is linked with methionine metabolism through Vitamin B12
  • 17. Glycine Tryptophan Formate N10-Formyl THF Purine (C2) Histidine FIGLU N5-FormiminoTHF N5,N10-Methenyl THF Serine N5,N10-Methylene THF Choline Betaine N5 Methyl THF B12 Methionine S-Adenosyl Methionine Homocysteine CH3- Transmethylation Formylmethionine Purines (C8) Serine Thymidylate Major sources Major Products THF THF THF THF One Carbon Metabolism
  • 18.  Rich sources are green leafy vegetables such as spinach, cauliflower  Poor sources are liver, kidney, milk, fruits
  • 19. Men -100 µg/day Women -100 µg/day Pregnancy -400 µg/day Lactation -150 µg/day
  • 20.  Dietary deficiency is the most common cause of folic acid  Dietary deficiencies are caused by  Inadequate intake seen in alcoholics  Overcooking of food resulting in loss of folic acid activity  Impaired absorption due to small intestinal diseases,  Drugs interfere with folic acid absorption- sulfamethaxazole
  • 21.  Increased demand of folic acid seen in pregnancy  Hemolytic anemia  Hence folic acid preparations are prescribed in pregnancy &hemolytic anemia  Other causes  Loss of folic acid seen in patients undergoing dialysis  Impaired synthesis of active form seen in patients receiving folic acid antagonists such as methotrexate
  • 22.  Megaloblastic anemia characterized by hyperchromic macrocytic anemia (due to maturation bloked)  Magaloblastic changes are seen in bone marrow & mucosa  Patients look pale  Glossitis
  • 23.  Peripheral smear shows macrocytic hyperchromic anemia  Hypersegmentation of neutrophils is common
  • 24.  Bone marrow shows megaloblastic changes characterized by abnormally large size of erythroid cells with cytoplasmic maturation but impaired nuclear maturation due to defective DNA synthesis  Defective red cell production
  • 25.  Low plasma folic acid levels (<3ng/ml)  Low red cell folic acid levels (<150 ng/ml)  Normal plasma Vitamin B12 levels  Increased plasma LDH levels
  • 26.  FIGLU excretion test:-  Folic acid deficiency is associated with increased excretion of formiminoglutamate (FIGLU) in urine  Due to impaired conversion of FIGLU to glutamate in a reaction requiring FH4 Histidine FIGLU Formimino FH4 Histidine Glutamate FH4 FIGLU Formimino FH4 Glutamate FH4 Urine Folic acid deficiency
  • 27.  Folic acid supplementation during pregnancy helps to prevent neural tube defects  Mainly involved in brain & spinal cord  Science, folic acid involved in nucleic acid & amino acid metabolism  Deficiency results in impaired & aberrant neural development
  • 28.  Homocysteine is a risk factor for CHD  Folic acid is required for conversion of homocysteine to methionine  Deficiency is associated with increased plasma levels of Homocysteine  Folic acid suplementation decreases plasma homocysteine levels  Homocysteine levels are also increased in Vitamin B12 & Pyridoxine deficiency
  • 29.  Aminopterin & Amethopterin (methotrexate)  Aminopterin & Amethopterin (methotrexate) competitevely inhibit the enzyme dihydrofolate reductase in humans  It impaires the formation of active form of tetrahydrofolate from dihydrofolate  Significance:-  During the conversion of deoxyuridylate to deoxythymidylate, dihydrofalate is formed, utilizes N5,10 methylene FH4
  • 30.  Deoxythymidylate is required for DNA synthesis  Folic acid antagonists will block DNA synthesis & inhibit cell division  Clinical uses:-  Aminopterin & Amethopterin (methotrexate) inhibit DNA synthesis in cancer cells  Used in treatment of cancer  Particularly leukemia & choriocarcinoma
  • 31.  It is a folic acid antagonist & it inhibits the bacterial dihydrofolate reductase  Thus impairs the deoxythymidylate synthesis leading to decreased synthesis of DNA  It is mainly used in bacterial infections
  • 32.  Harper’s Biochemistry 25th Edition.  Fundamentals of Clinical Chemistry by Tietz.  Text Book of Medical Biochemistry-A R Aroor.  Text Book of Biochemistry-DM Vasudevan  Text Book of Biochemistry-MN Chatterjea  Text Book of Biochemistry-Dr.U.Satyanarana

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