Metab II Exam II Pyridoxine B6 6 Vitamers Sources Beef salmon light meat chicken whole grain products vegetables fruits nuts fortified cereals Deficiency Rare decrease in heme production 1950s deficiency occurred in infants because of severe heat treatment of infant milk At risk Elderly alcoholics long term dialysis Medications isoniazid penicillamine corticosteroids anticonvulsants Treatment Supplements of pyridoxine hydrochloride UL 100 mg d for adults Toxicity peripheral and sensory neuropathy unsteady gait paresthesia impaired tendon reflexes demyelination and degeneration of sensory fibers degeneration of dorsal root ganglia Supplements pyridoxine hydrochloride Absorption 1 Intestine Brushborder phosphorylated vitamers of B6 must be dephosphorylated PNP PLP PMP PN PL PM Alkaline phosphatase zinc dependent enzyme hydrolyzes phosphate group to yield either PN PL or PM other intestinal phosphatases 2 Jejunum 3 Enterocyte PL PN PM passive diffusion we absorb approx 75 of B6 eaten intestinal cell mostly rapidly absorbs B6 via passive diffusion Tissues Liver takes up B6 by passive diffusion stores 5 10 of vitamin site of metabolism of vitamin B6 PN PL PLP PMP PL PLP FMN dependent kinase PLP enzyme FMN dependent kinase enzyme alkaline phosphatase pyroxidine kinase Circulation from the plasma unphosphorylated vitamers may be taken up by RBCs and converted to PLP and bound to hemoglobin only unphosphorylated forms are taken up by tissues PLP in the blood is hydrolyzed by alkaline phosphatase prior to cellular uptake In cells PL is phosphorylated by pyridoxine kinase ATP dependent reaction Muscle the major storage site for B6 Stores 75 80 of vitamin B6 most B6 in muscle as PLP bound to Glycogen Phosphorylase Phosphorylation of B6 prevents its diffusion out of the cell binding of the protein prevents hydrolysis by phosphatases Functions 100 enzymes most involved in amino acid metabolism use PLP co enzyme Roles labilizes all the bonds around the alpha carbon of the amino acid the specific bond that is broken is determined by the catalytic groups of the particular enzyme to which PLP is attached Decarboxylation neurotransmitter synthesis Glutamate GABA L dopa dopamine dopa made from tyrosine Cleavage Serine Hydroxymethyltransferase cleaves hydroxymethyl group off of methyl tetrahydrofolate and attaches to serine to form glycine requires PLP Methionine Cysteine Enzymes cystathionine synthase and Cystathionine Lyase both of these require PLP Formation and Maturation of Erythrocytes Proerythroblasts Basophilic Erythroblasts Polychromatophil erythroblast orthochromatic erythroblast reticulocyte erythrocytes Folate and Vitamin B12 deficiency microcytic Hypochromic Anemia very small RBC megaloblastic Anemia very large RBCs fewer than normal Synthesis of porphyrins PLP coenzyme for Gamma aminolevulinic acid synthase PLP synthesis of niacin from tryptophan 3 hydroxykynurenin 3 hydroxyanthranilate Enzyme PLP Byproduct Niacin carnitine a non protein Nitrogen containing compound required for FA oxidation Taurine a neuromodular compound generated from cysteine Assessment Urine excreted in urine as 4 pyridoxic acid also formininoglutamate urine test RBC amino transferase activities Plasma PLP Indirect tests tryptophan load test measures xanthurenic acid excretion following tryptophan loading methionine load test necessary for detection of hyperhomocysteinemia Deficiency Symptoms Adults Sleepiness fatigue cheilosis glossitis stomatitis Hypochromic microcytic Anemia altered calcium and magnesium metabolism hyperhomocysteinemia Infants Neurological problemsd Abnormal EEGs Seizures convulsions Commercial Claims for supplementation of B6 carpal tunnel syndrome PMS Depression Muscular fatigue paresthesia autism hyperhomocysteinemia Commercial Claims for supplementation Niacin control cholesterol medications in form of nicotinic acid circulatory problems niacin acts as a vasodilator fight depression ease symptoms of arthritis slow progession of type 1 diabetes treat tinnitus persistent ringing in ears Riboflavin prevents the development of cataracts combat migraines treat skin blemishes Thiamin depression anxiety and stress congestive heart failure heartburn Pantothenic Acid Migraines Chronic Fatigue syndrome may help with smoking and alcohol cessation heartburn allergy symptoms and asthma control cholesterol Biotin diabetes brittle nails dull hair Folate B9 Sources Mushrooms green vegetables peanuts legumes fruits fortified cereals breads grains Deficiency some cancers especially colon cancer neoplastic changes in cells neural tube defects inhibits maturation of bone marrow cells and other rapidly dividing cells cells remain large immature contain nucleus At risk malabsorption diseases excessive alcohol consumption medications Phentoin methotrexate Folic acid oxidized form found in foods and supplements Folate reduced form found naturally occurring in foods and biological tissues Folate main function DNA synthesis cell divison continued formation of RNA leads to excessive production of hemoglobin 50 in diet is bioavailable intestinal pH genetic variations in enzymatic activity dietary consitituents inhibitors food matrix can be lost in cooking but amount lost depends on form of vitamin 96 bioavailable in cooked lima beans 25 in romaine lettuce when fortified sources consumed with natural sources consume 85 is bioavailable supplement form is almost completely bioavailable Structure we can make all three pieces of the structure but we cannot link them together Forms Polyglutamates coenzyme forms additional glutamate residues attached to glutamate Monoglutamates transport forms Biologically active form is Tetrahydrofolate THF Digestion and Absorption Eaten as polyglutamates Conjugases cleave polyglutamates into monoglutamates Found in jejunal mucosa brush border zinc dependent pancreatic juice bile conjugase inhibitors legumes lentils cabbage oranges Enterocyte folate binding proteins Aka folate carriers folate receptors sodium dependent active transport to allow folate into cell may also transport within cell most absorption in jejunum Folate and dihydrofolate reduced to THF NADPH dependent dihydrofolate reductase cytoplasmic enzyme THF methylated to 5 methyl THF or formylated Diffusion accounts for some absorption particularly pharmacological doses Portal Circulatoin transport into circulation is carrier dependent 5 methyl THF dihydrofolate formylated forms Liver uptake is carrier mediated by folate
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