MCAT Biomolecules: Water & Fat Soluble Vitamins Dr. Phillip Carpenter medpathwaymcat Med-pathway Vitamins/Co-factors Water Soluble: Vitamin B1, B6, B7, B12, C Fat Soluble: A, D, E, K Vitamin B12 or Cobalamin 1. Methionine Synthase 2. Methylmalonyl Co A mutase X N N Co Co N N N X = CH3 (1) = 5’ Deoxyadenosine (2) = CN- Corrin Ring with 4 Pyrrole Groups B12 & The GI Tract MOUTH STOMACH R B12 B B12 P 12 P IF R R R IF DUODENUM ILEUM B P = B12 bound protein LIVER 12 IF R = Haptocorrin IF = Intrinsic Factor Vitamin B12 & Tetrahydrofolate One Carbon Transfer THF Methionine 5-CH3-THF Vit B12 Methionine Synthase THF Me-B12 Homocysteine THF & One Carbon Transfer N5 Formyl THF N5 N10 Methylene THF N5 N10 Formyl THF N5 methyl Formyl-THF Methylenyl-THF Methylene-THF 5-CH3-THF Irreversible Step Formyl-THF: Methionyl-tRNA formyltransferase Folate Trap Methylene-THF: Thymidylate synthase 5-CH3-THF: Methionine synthase B12 Deficiency 5-CH3-THF Vit B12 Methionine SAM Methionine Synthase THF Me-B12 Homocysteine SAH Formyl-THF Methylenyl-THF Methylene-THF 5-CH3-THF B12 Deficiency 5-CH3-THF Vit B12 Methionine SAM Methionine X Synthase THF Me-B12 Homocysteine SAH B12 deficiency = Folate deficiency Formyl-THF Methylenyl-THF Methylene-THF 5-CH3-THF B12 Deficiency & Homocystinuria Dietary Methionine 5-CH3-THF Vit B12 Methionine SAM Methionine X X Synthase THF Me-B12 Homocysteine SAH CardiovasCular X B12 deficiency = Folate deficiency Neurological Formyl-THF Methylenyl-THF Methylene-THF 5-CH3-THF MTHFR Deficiency 5-CH3-THF Vit B12 Methionine SAM Methionine Synthase THF Me-B12 Homocysteine SAH Methylenetetrahydrofolate Reductase (MTHFR) Deficiency Formyl-THF Methylenyl-THF Methylene-THF X 5-CH3-THF MTHFR Deficiency & Homocystinuria Dietary Methionine 5-CH3-THF Vit B12 Methionine SAM Methionine X SynthaseX THF Me-B12 Homocysteine SAH X B12 deficiency = CardiovasCular Folate deficiency Neurological Methylenetetrahydrofolate Reductase (MTHFR) Deficiency Formyl-THF Methylenyl-THF Methylene-THF X 5-CH3-THF Folate Trap MTHFR Deficiency & Homocystinuria Dietary Methionine 5-CH3-THF Vit B12 Methionine SAM Methionine SynthaseX THF Me-B12 Homocysteine SAH B12 deficiency CardiovasCular = Folate deficiency Neurological Methylenetetrahydrofolate Reductase (MTHFR) Deficiency Formyl-THF Methylenyl-THF Methylene-THF X 5-CH3-THF Folate Trap Folate & DNA Synthesis Folate & DNA Synthesis Methotrexate X http://www.va.gov/telepathvisn6/megalops. GIF Pyridoxal phosphate (PLP or Vitamin B6) Catalyzes over 140 reaCtions! Lys Commonly linked to Lysine Reaction Types on AA substrates 1. Decarboxylation 2. Transamination 3. Racemization 4. Deamination TRANSAMINATION α-ketoglutarate Glutamate - COO- O COO O + - - O C CH2CH2 C O H3N C CH2CH2 C O H - COO COO- + H3N C CH2 O C CH2 H Transaminase L-Phenylalanine Phenylpyruvate Biotin + ADP The Biotin Cycle Apoenzyme Holocarboxylase Synthetase ATP Biotinidase AMP + PPi Free Biotin Pool BioCytin Holoenzyme-Lys - Activated ATP + HCO3 Peptide-Lys Carboxyl Dietary Biotin ADP + Pi Substrate-CO2 Gluconeogenesis Substrate Fatty acid synthesis Catabolism of some AA Holoenzyme-Lys The Biotin Cycle Apoenzyme Holocarboxylase Synthetase ATP Biotinidase AMP + PPi Free Biotin Pool BioCytin Holoenzyme-Lys - Activated ATP + HCO3 Peptide-Lys Carboxyl Dietary Biotin ADP + Pi Substrate-CO2 Gluconeogenesis Substrate Fatty acid synthesis Catabolism of some AA Holoenzyme-Lys Thiamine Vitamin B1 * Pyruvate Dehydrogenase Complex (PDC) NAD+ + H+ * * NADH Pyruvate Acetyl CoA + CO2 Breaking NAD+ + H+ NADH C-C bond Isocitrate ⍺-ketoglutarate + CO2 * * * Lipoic Acid LIPOIC ACID LipoiC ACid E2 R1 R1 * * * 3 _ * R 2 R2 ResonanCe Stabilized Carbanion Lipoic Acid LIPOIC ACID Lipoic Acid 7 5 6 3 8 4 1 LIPOIC ACID 2 Lipoic Acid LIPOIC ACID ENZYME LIPOYLLYSINE E2 ENZYME Pyruvate Dehydrogenase Complex BASE: R1 5 E2 _ 4 R2 + * E2 * R1 _ R2 Pyruvate Dehydrogenase Complex R1 5 _ R2 + * * .. CoASH 6 + CoAv E2 * * Pantothenic Acid Coenzyme A (CoASH) Pantothenic Acid (Vitamin B5) Acetylation Acyl Group Carrier Acetyl CoA Coenzyme A R1 5 _ R2 + * * E2 .. NADH 7 CoASH R1 6 NAD+ + v E2 * * CoA R2 Pyruvate Dehydrogenase Complex Pyruvate Thiamine BASE: R1 _ R2 R1 5 1 E2 _ 4 R1 R2 + R 2 E2 2 .. CO2 7 R1 NADH CoASH R1 6 3 _ NAD+ + CoAv R E2 2 R2 Vitamin C 2 GSH GSSG 2H+, 2e- Ascorbic Acid Dehydroascorbic Acid 2 GSH γ-Glu-Cys-Gly Oxidized Glutathione Vitamin C pKa = 4.1 - Ascorbic Acid (AscH2) Ascorbate (AscH ) Hexose derivative Vitamin C pKa1 = 4.1 - Ascorbic Acid (AscH2) Ascorbate (AscH ) Hexose derivative pKa2 = 12 Ascorbate (Asc-2) Vitamin C pKa1 = 4.1 H+ + e- - . Ascorbic Acid (AscH2) Ascorbate (AscH ) Ascorbate Radical (AscH ) Hexose derivative . - pKa = 12 R + e R Donates e- to free radiCal Ascorbate (Asc-2) Vitamin C Reactions AsCorbate DehydroasCorbate O2 H2O Dopamine Dopamine Beta-Hydroxylase Norepinephrine (Monooxygenase) Proline Hydroxyproline ⍺-KG Succinate O2 CO2 Lysine Hydroxylysine Fe+2 Fe+3 Collagen Modified Collagen DehydroasCorbate AsCorbate Fat Soluble Vitamins Vitamins A, K, E, D Vitamin A Vitamin A & Vision Vitamin K Vitamin K & Clotting Vitamin E (Tocopherols) . LOO + a-toCopherol–OH / LOOH + a-toCopherol–O LOO. Vitamin D +2 Stimulates uptake of Ca , PO4 in intestines (CalCitriol) CalCidiol Vitamin D binds to the Vitamin DBP Vitamin D +2 Stimulates uptake of Ca , PO4 in intestines + PTH (CalCitriol) CalCidiol Vitamin D binds to the Vitamin DBP Vitamin D Transcription Differentiation Proliferation Pol II Apoptosis VDR RXR 1, 25(OH2)D3 RXR VDR 1, 25(OH2)D3 VDR 1, 25(OH2)D3 1, 25(OH2)D3 DBP Parathyroid Hormone 4 Parathyroids Low serum Ca+2 PTH OsteoClasts Intestines: Ca+2 and PO -3 4 absorbs Ca+2 released from bone -3 and PO4 Kidneys Liver 25(OH)D3 1, 25(OH)2D3 1, 25(OH)2D3 +2 UrineKidney Ca -3 Urine PO4 Bone Structure OSTEON Canaliculi CORTICAL Lacunae SPONGY (Osteoblasts) Haversian Canal Lamellae (Blood, lymph, nerves) Workshop Passages www.med-pathway.com/register.