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