9 GIT5 Absorption and Metabolism of Vitamins.pdf

IMED3112: Integrated Medical Systems 2 GIT Physiology Lecture 5 A&M of Vitamins Rob White Physiology, UWA [email protected] Outcomes 1. Outline the different mechanisms used for absorption and distribution of vitamins. 2. Describe the chemical properties of vitamins & understand how this inf...

IMED3112: Integrated Medical Systems 2 GIT Physiology Lecture 5 A&M of Vitamins Rob White Physiology, UWA [email protected] Outcomes 1. Outline the different mechanisms used for absorption and distribution of vitamins. 2. Describe the chemical properties of vitamins & understand how this influences their metabolism 3. Outline metabolic pathways of specific vitamins 4. Describe the functions of specific vitamins 5. Outline the biological effects over under/over supply of different vitamins Vitamins • 1912 - Casimir Funk: B1 in rice bran "Vitamin" (vital amines). • Organic compounds req.d as a nutrient in tiny amounts. • Cannot be synthesized in sufficient quantities, and must be obtained from the diet – Vitamin D??? • Vitamins have diverse biological functions: – – – – hormone-like functions as regulators of mineral metabolism (vit. D), regulators of cell/tissue growth/differentiation (vit. A) antioxidants (vit. E, C) enzyme cofactors (tightly bound to enzyme as a part of prosthetic group, coenzymes) Coenzymes & enzyme cofactors AH2 + NAD+  NADH + H+ B + NADH + H+  BH2 + NAD+ Transcriptional or post-transcriptional regulators • Bind to receptors that form a transcriptional regulatory complex (A, D) that changes gene expression – D = Vitamin D receptor is a Transcription Factor – A = Retinoic X receptor is a Transcription Factor • Modify the structure of proteins to activate their function. – K = glutamate residue carboxylation Deal with oxidative stress O2 •O 2 •OH H2O2 ROS DNA lipids proteins • Reactive oxygen species (ROS) cause damage – Proteins and sugars (glycation) – DNA (mutations) – Membranes (lipid peroxidation) Vitamin classification Lipid-soluble vs water-soluble Lipid-soluble vitamins (A, D, E & K) • hydrophobic compounds, absorbed efficiently with lipids • transport in the blood in lipoproteins or attached to specific binding proteins • more likely to accumulate in the body • more likely to lead to toxicity = hypervitaminosis Vitamin classification Water-soluble vitamins – 8x B vitamins & vitamin C • hydrophilic compounds dissolve easily in water • not readily stored, excreted from the body • consistent daily intake is important – deficiency problems Many types of water-soluble vitamins are synthesized by bacteria/fungi. Water soluble vitamins         Vitamin B1 (thiamin) Vitamin B2 (riboflavin) Vitamin B3 (niacin) Vitamin B5 (pantothenic acid) Vitamin B6 (pyridoxine and pyridoxamine) Vitamin B7 (biotin) Vitamin B9 (folic acid) Vitamin B12 (cobalamin) …. & jolly old….  Vitamin C (ascorbic acid) 1. Coenzymes & enzyme cofactors B1 B2 B3 B6 B9 B7 B5 B3 B6 B6 B1 B2 B2 B3 B9 B12 B12 B3 B5 B12 B7 B2 B12 B2 B5 B3 B12 B3 B6 B6 B7 B1 B5 B2 B3 B3 B6 B3 B3 B1 B2 B2 B12 B5 B7 B6 B6 B1 (thiamin) • Roles – CHO & AA metm, DNA/RNA/neurotransmitter synthesis • Active coenzyme (thiamin pyrophosphate, TPP) – TPP catalyses oxidative decarboxylation of α-ketoacids – pyruvate dehydrogenase in CHO metabolism – a-ketoglutarate dehydrogenase → TCA cycle • Deficiency = Problems with energy and neurotransmitter production • beriberi – CNS problems  Memory loss (amnesia), confusion (delirium), ataxia (gait coordination). – Peripheral neuropathy  muscle weakness, muscle wasting – Wernicke-Korsakoff syndrome  alcohol-induced dementia (same symptoms) • No toxicity symptoms (VERY water soluble) B2 (riboflavin) • Coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotid (FAD). • FMN and FAD act as prosthetic groups of many redox enzymes – coenzymes in proton transfer – FMNH2 & FADH2 – succinate dehydrogenase – TCA cycle – acyl CoA-dehydrogenase – β-oxidation of FA – NADH-dehydrogenase – mitochondrial respiratory chain • B2 deficiency – RARE! – Problems with proliferation in high cell turnover tissues • Inflammation of the lining of mouth and tongue. • Dry and scaling skin- keratitis, dermatitis and iron-deficiency anaemia – No toxicity B3 - niacin • 2 forms – nicotinic acid & nicotinamide. • NAD and NADP → coenzymes in CHO, lipids, AA metabolism (TCA cycle). • Biosynthesis: – Liver can slowly synthesize Niacin from tryptophan (essential AA) • Deficiency: Effects tissue with high energy requirements or cellular turnover – Pellagra: A serious deficiency of niacin. – "the four D's": diarrhea, dermatitis, dementia, and death. – Very rare now  alcoholics, strict vegetarians, v poor nutrition (corn: low tryptophan). – No toxicity B5 – Pantothenic Acid • acetyl-CoA – consists of pantoic acid and β-alanine. • Co-A is essential for: – TCA cycle – Metabolism of fatty acids. – Formation of sterols (cholesterol & 7-dehydrocholesterol) – Acetylcholine production • Very, very, very, very, very, very, very rare in humans – – – – – “Pantothen” Greek = “everywhere”! General metabolic deficiencies leads to paresthesia (pins and needles). Disorders of the synthesis of acetylcholine – neurological symptoms. No toxicity (even a 2000x the RDI) Vitamin B6 – pyridoxine (PLP) • Group of 3 related compounds • Precursor of active coenzyme pyridoxal phosphate – PLP. – Coenzyme in amino acid synthesis & gluconeogenesis. • Essential for: – RBC metabolism, haemoglobin formation. – Neurotransmitter biosynthesis. • Deficiency: • Anaemia (RBCs and Hb) • Neurological problems (NTs) – seizures, confusion, depression • Inflammation of the GI tract (stomatitis, glossitis) and skin (dermatitis) • Toxicity exists!!! (>200 mg/day) Vitamin B7 - biotin • Prosthetic group of several ATP-dependent carboxylase enzymes (pyruvate carboxylase, acetylCoA carboxylase). • Coenzyme for FA synthesis, gluconeogenesis, CHO, fat, and protein metabolism • Deficiency = RARE • • • • Inflammation of GI tract and skin Consumption of raw eggs (contain avidin – binds biotin) Produced by gut bacteria No toxicity. Vitamin B9 – folic acid • Folic from “foliage” – found in green leaves • Ingested folate (Pteroylglutamic acid) must be de-glutamated, then hydrated  tetrahydofolate (THF  active metabolite) • THF is coenzyme of many transferases. – Essential in purine and pyrimidine (DNA & RNA) synthesis • Deficiency (very rare – high turnover / RNA synthesis) – RBCs  anaemia (macrocytic = immature RBCs) – Nervous system  depression, confusion, delirium • Deficiency in pregnant women can lead to birth defects – neural tube defects (spina bifida). Vitamin B12 - cobalamin • Catalyses the rxns of two enzymes: – Methionine synthase (DNA synthesis). – methylmalonyl-CoA mutase (MMCoA  succinylCoA) = energy metabolism. • Essential for energy metabolism, purine + pyrimidine synthesis – Same as B9 – RBC maturation, cell growth, nervous system maturation • Deficiency (high turnover / RNA synthesis) – RBCs  anaemia (macrocytic = immature RBCs) – Nervous system  fatigue, amnesia, depression, delirium • Common: >40% of vegetarians, 80% of vegans (Pawlak (2013) Nutrition Reviews. 71). – receptor-mediated uptake with intrinsic factor 2. Antioxidants • E - lipid-soluble: – lipid peroxidation, membranes, membrane-bound proteins • C - water-soluble: – free radicles in solution (DNA, non membranebound proteins, etc.) Vitamins C & E as antioxidants C - Ascorbic acid • The principal water-soluble antioxidant and free radical scavenger • Also Involved in: – Cofactor in the synthesis of noradrenaline from dopamine. – Leukocyte mobility. – Synthesis of collagen. • Deficiency = Scurvy = C over 3-5 months. – hence the name “a-scorbic” = “anti-scurvy” vitamin. – Neuronal problems - fatigue, decline in psychomotor performance and motivation, dyspneoa. – Collagen problems - spongy gums, and bleeding from all mucous membranes (loss of teeth). E - tocopherol • A family of tocopherols (α−, β−, γ−, δ−). – Highest biological activity= αtocopherol (also most common). Antioxidant • Prevents lipid peroxidation • Stops free radical reactions • Deficiency – impairment of fertility in men – peripheral neuropathy – Anaemia, diminished RBC life span All from free radical damage virtually never occurs: a-TTP mutations, fat malabsorption • toxicity is rare; increased bleeding. 3. Regulators + extras! A: Retin-ol/-al/-oic acid • Precursors: – Carotenoids (plants), Retinol esters (animals) • Functions – Transcriptional regulation: Retinoic X receptor is a TF • Immune function, embryonic development and cellular differentiation – visual pigment (Forms rhodopsin in retinal photoreceptors) • Toxicity – Acute symptoms - headache, vomiting, impaired consciousness. – Chronic intoxication – weight loss, vomiting, joint pain, blurred vision, hair loss, excessive bone growth • Both excess and deficiency in pregnancy are teratogenic (“monster-forming”) – Chemotherapeutic – 13-cis-Retinoic Acid (isotretinoin) D = not a vitamin! • Synthesis in the skin: 7-dehydrocholesterol + UVB (~300 nm) → D3 • further transformation by hydroxylase enzymes: • Liver  25-hydroxy-D3 (calcidiol) • Kidneys  1,25-dihydroxy D3 (calcitriol = ACTIVE). (calcidiol) 25-hydroxyvitamin-D3 (calcitriol) 1,25-dihydroxyvitamin-D3 D: Calcitriol •Transported in the blood on a carrier • vitamin-D binding protein, VDBP. • Binds vitamin D receptor = transcription factor • Regulates Ca2+ levels • increase Ca2+ absorption (gut) • Switches on genes of Ca2+ transporters (TRPV6) and Ca2+ binding proteins (calbindin) • Deficiency = Ca2+ deficit • Via malabsorption or lack of UVB (λ~300nm) sunshine • “rickets” - low Ca2+ levels , which results in: • soft and pliable bones = impaired ossification • Osteomalacia in adults (after closure of epiphyseal plates) Enterocyte Calcium Absorption Blood Lumen Vitamin D responsive Calbindin TRPV6 Ca2+ PMCA Calcium ATPase Enterocyte ATP ase Ca2+ Ca2+ Ca2+ NCX sodiumcalcium antiporter Ca2+ 3x Na+ Albumin Paracellular Ca2+ Vitamin D independent Ca bound to fiber, phytate, oxalate, fatty acids • TRPV6 (CAT1) is a Ca2+ channel protein located in the brush border of mucosal cell • Calbindin is a small (9 kD) protein in the cytosol of mucosal cells • VitD (calcitriol) activates transcription of both! Vitamin K - Koagulationsvitamin • 2 forms – both active Vitamin K1 – K1 (phylloquinon) – plants – K2 (menaquinon) – converted from K1 by animals/bacteria, synthesised by bacteria Vitamin K2 • Coenzyme (e- donor) for γ-glutamyl carboxylase – Carboxylates glutamate residues in specific proteins – Glutamate  γ-carboxy-glutamate (“Gla”) = activation of function inactive active Vitamin K • Specific “vitamin K-dependent” proteins – Blood coagulation: prothrombin (factor II), factors VII, IX, X, & proteins C, S, Z – Bone metabolism: osteocalcin, matrix Gla protein (MGP), periostin. Deficiency • Rare: vitamin K is abundant in the diet • Cause? fat malabsorption, liver failure. • Blood clotting disorders – dangerous in newborns, lifethreatening bleeding (hemorrhagic disease of the newborn). • Osteoporosis due to decreased activity of osteoblasts. Toxicity? None! Vitamin absorption Lipophilic vits (A, D, E, K) • • • • Co-absorption with digested fat in bile salt micelles Vulnerable because of insolubility Bile duct obstruction  Vitamin K (required for blood clotting) Transported around in lipoproteins or on transport proteins (or both) Water-soluble vitamins (Bs & C): • • specific transporters (B9 requires a bit of modification…) Except B12 = no transporter? Slide 31 Water soluble vitamins: specific mechanisms • B1 (Thiamine): Na+-independent, pH dependent, thiamine transporter (THTR-1/2). • B2 (Riboflavin): Na+-independent (SLC52A3) • B3 (Niacin): Na+-dependent, pH dependent (SMCT1) • B5 (Pantothenic acid): Na+-dependent multivitamin transporter (SMVT) • B6 (Pyridoxamine): Na+-independent, pH dependent (TPN1) • B7 (Biotin): Na+-dependent, multivitamin transporter (SMVT). • C (Ascorbic acid): Na+-dependent (SVCT), dehydro-L-ascorbic acid uses GLUT-1/3/4 B9 Folate (pteroyl-L-glutamic acid) Removes all but 1 glutamate residues methyltransferase CH3-THF methyltetrahydrofolate (bioactive) Vit B12 (cobalamin) TCII: transcobalamin 2 IF: intrinsic factor Summary • Lipid-soluble vitamins are stored in body fat, thus have accumulative toxic effects (hypervitaminosis). • Water-soluble vitamins are readily cleared  less likely to have toxic effects, but require daily supply • Vitamins are involved in specific metabolic pathways, and the biological effects observed in deficiency are metered through these metabolic pathways