Biochemistry Lecture: Vitamins, Minerals & Trace Elements PDF

BIOCHEMISTRY LECTURE | TRANS #1 LE Vitamins, Minerals & Trace Elements KAREN M. FAUSTINO, MD | Le...

BIOCHEMISTRY LECTURE | TRANS #1 LE Vitamins, Minerals & Trace Elements KAREN M. FAUSTINO, MD | Lecture Date (01/17/2024) | Version #2 04 8n OUTLINE I. Vitamins III. Fat-soluble vitamins A. Introduction A. General Characteristics II. Water-soluble vitamins B. Vitamin A (Retinoids) A. General Characteristics C. Vitamin D and Calcium B. Thiamin or Thiamine D. Vitamin E (Vitamin B1) E. Vitamin K C. Riboflavin (Vitamin B2) IV. Trace Elements D. Niacin (Vitamin B3) A. Iron E. Pantothenic acid (Vitamin B. Iodine B5) C. Zinc F. Pyridoxine (Vitamin B6) D. Copper G.Biotin (Vitamin B7) E. Chromium H. Folic acid (Vitamin B9) F. Selenium I. Cobalamin (Vitamin B12) G.Manganese J. Ascorbic acid (Vitamin C) H. Molybdenum I. Fluoride J. Boron V. Case study VI. References VII. Review questions VIII. Appendix Figure 1. Classification of Vitamins[Dr. Faustino’s PPT] ❗️ Must know 💬 Lecturer 📖 Book 📋 Previous Trans II. WATER-SOLUBLE VITAMINS SUMMARY OF ABBREVIATIONS A. GENERAL CHARACTERISTICS Ca2+ Calcium Extracted from food with aqueous solvents/hydrophilic Function mainly as enzyme cofactors PTH Parathyroid Hormone Can check vitamin status by measuring enzyme activity in isolated LEARNING OBJECTIVES RBC ✔ Classify the vitamins according to their solubility properties Toxicities are rare because high levels that are beyond the renal ✔ ✔ Compare the characteristics of the water- and fat-soluble vitamins Relate the biochemical/metabolic roles of the individual vitamins ❗️ threshold are rapidly excreted Readily excreted via renal excretion (urination) ▪ Results to low storage of these vitamins in tissues to their chemical structures and unique features → Labile metabolic stores ✔ Diagram some general areas of metabolism in which these ▪ The body cannot store water-soluble vitamins except for vitamins participate in Vitamin B9 and B12 ✔ Recognize deficiency and toxicity states ▪ Overall, the body does not store water-soluble vitamins ✔ Identify chief sources very well ✔ Resolve certain issues on vitamin supplementation The depletion of these vitamins can occur rapidly with inadequate ✔ Describe the role of minerals in metabolism diets → Can take place in a few months or even weeks I. VITAMINS → Must have a regular supply of these vitamins A. INTRODUCTION Deficiency of a single vitamin is rare Organic micronutrients → Poor diets are often associated with multiple deficiency states → Made up of considerable amounts of carbons and overlapping symptoms Essential → Since vitamins functions in processes that involve energy → Cannot be synthesized by humans generation and hematopoiesis, early symptoms are seen in → Supplied by the diet or supplementation areas where there is high energy demand such as the Serve various biochemical functions: nervous tissues and rapidly growing tissues → As coenzymes, cofactors, hormones, metabolic regulators, etc. ▪ Neurologic symptoms: Small dietary requirements − Peripheral Neuropathy - Tingling sensation in the → Vitamin deficiency states are common and can lead to specific extremities clinical syndromes but can be prevented by diet provision. − Confusion ❗️ → Most of the time excesses in vitamins do not commonly occur Contain no calories → Helps in extracting energy from macronutrients such as − Depression − Lack of coordination − Body Malaise carbs, proteins, and lipids − Others: rapidly growing tissues Two classes: o Dermatitis → Water-soluble: o Glossitis ▪ B & non-B vitamins o Cheilitis − Non-B vitamins: Ascorbic Acid or Vitamin C → Fat-soluble: A, D, E & K Space intentionally left blank LE 1 TG | A. Palima, Kat. Paradero, Kar. Paradero, L. Paralejas, TE | D. Patajo, E. Punzalan, AVPAA | C. Rival PAGE 1 of TRANS 1 M. Pascual, M. Pasia, J. Pastor, *D. Patajo, I. Tan, J. Tan, KC. F. Rollo, J. Tan, M. Tejano 31 Tan, KM. Tan., *Tanchuling, Tanodra, Tayag, Tejano BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD B. THIAMIN OR THIAMINE (VITAMIN B1) → Peripheral neuropathy Made up of a pyrimidine ring and a substituted thiazole ring ▪ Due to impaired nerve transmission in the neural tissue connected by a methylene bridge because energy producing pathways are particularly important in the CNS ▪ May also be due to the accumulation of pyruvate and lactate in the neural tissues Figure 2. Chemical structure of Thiamin (VIT B1)[Dr. Faustino’s PPT] Thiamine Pyrophosphate (TPP) is the biological active form of Vitamin B1 → Has an important role in energy yielding metabolism (carbohydrate and amino acid metabolism) ▪ Mainly for carbohydrates Has 2 additional phosphate groups so it is also called Thiamine diphosphate Figure 4. Summary of Important Reactions Involving Thiamine[Devlin] Thiamine is also a cofactor in the catabolism of amino acids. The products of which could either be glucogenic or ketogenic precursors. Figure 3. Thiamin (VIT B1) and TPP[Dr. Faustino’s PPT] Thiamine requirement increases as carbohydrate intake increases → TPP is a coenzyme for transketolase, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase which ❗️ are needed in the reactions for processing carbohydrates RBC transketolase is commonly used for measuring the status 📖 of thiamine in the body There are 2 enzymes in the TCA cycle that requires TPP as a coenzyme [Devlin] → Pyruvate Dehydrogenase = conversion of Pyruvate to Acetyl-CoA → α-Ketoglutarate dehydrogenase = conversion of α-Ketoglutarate to Succinyl-CoA ▪ There is reduced oxidative decarboxylation of α-keto acids when α-Ketoglutarate dehydrogenase activity is down Other references state that there is a third reaction in the TCA cycle requiring thiamine which is isocitrate dehydrogenase → Isocitrate dehydrogenase = conversion of isocitrate to Figure 5. Role of TPP in the Catabolism of the Branched-Chain α-Ketoglutarate Amino Acids[Dr. Faustino’s PPT] Decrease in Thiamine Pyrophosphate would lead to: → Decrease ATP synthesis = Weakness MUST KNOW ▪ Decrease in cellular energy generation Vitamins status in the body can be checked by measuring the → Increase production of lactate/pyruvate = lactic acidosis activity of the enzyme for which that vitamin acts as a ▪ Due to impaired conversion of pyruvate to acetyl-CoA coenzyme or it can be measured directly (e.g., High Pressure ▪ There is a buildup of substrate when the reaction does not Liquid Chromatography [HPLC] to find vitamin levels in the proceed body ▪ Especially true in patients who have thiamin deficiency and THIAMIN: FOOD SOURCES is taking a relatively high carbohydrate diet Enriched bread and cereals Unpolished rice, rice polishings, whole wheat bran Pork, fish, liver Legumes, peas, seeds, nuts BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 2 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD THIAMIN DEFICIENCY A concern for those on restricted diets → E.g., elderly patients, low income patients Alcoholics → Problems with multiple vitamin deficiencies such as thiamine and pyridoxine (Vitamin B6) deficiency causing neurologic effects or folate and pyridoxine deficiency leading to hematologic problems Symptoms of Thiamine Deficiency → Loss of appetite → Constipation → Nausea As short as 2 weeks thiamine can be depleted and may cause symptoms already Figure 6. Riboflavin (VIT B2) - Structure[Dr. Faustino’s PPT] If moderately severe: → Wernicke-Korsakoff syndrome/ psychosis FMN and FAD are needed in ETC reactions ▪ Manifestations: → Riboflavin deficiency results in a decrease in ATP production − Mental confusion by the mitochondria via oxidative phosphorylation − Ataxia − Ophthalmoplegia - loss of eye coordination ▪ Commonly seen in chronic alcoholics − Due to impaired absorption of thiamine and liver cirrhosis ❗️ which can affect the storage of thiamine Responds to thiamine injections If severe: → Beriberi ▪ State of severe thiamine deficiency − First found among asians at the end of the 19th century where rice is a staple food ▪ Seen especially in groups relying exclusively on well polished or milled rice for food − when you remove the rice bran or the aleurone layer of the rice, the thiamine content is significantly reduced − Whole grains = higher thiamin content ▪ Infantile form of Beriberi manifests as: − Increased heart rate Figure 7. Role of FMN and FAD in Redox Reaction[Dr. Faustino’s PPT] − Vomiting − Restlessness Vitamin B2 also participates in the Citric Acid Cycle as FAD in − Convulsions the conversion of Succinate to Fumarate ▪ May be fatal if left untreated in infants ▪ Adult manifestations include: − Dry skin − Irritability − Muscle wasting/ atrophy − Weakness − Disorderly thinking − Progressive Paralysis ▪ “Wet Beriberi” : Beriberi with edema − Common form in alcoholics and is frequently associated with heart failure C. RIBOFLAVIN (VITAMIN B2) Figure 8. Role of FAD in the Citric Acid Cycle[Dr. Faustino’s PPT] Riboflavin is made up of ribitol (sugar) and heterocyclic flavin ring Vitamin B2 also plays a role in B-Oxidation of fatty acids as FAD Precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) → Vit B2 biologically active forms and they act as coenzymes and their partner enzymes are called flavoenzymes → The carbons in nitrogens encircled in Figure 6, participate in redox reactions and a functional part of the coenzyme. FMN and FAD are both capable of reversibly accepting 2 hydrogen atoms which are electron carriers to form FMNH2 and FADH2 → FMNH2 and FADH2 can donate the hydrogen atoms → Thus, FMN and FAD participate in redox reactions and these are essential for energy production and cellular respiration Space intentionally left blank Figure 9. Role of FAD in the B-Oxidation of Fatty Acids[Dr. Faustino’s PPT] BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 3 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD The oxidation of arginine to citrulline and nitric oxide is catalyzed Nicotinic acid and nicotinamide are the two vitamin active by FAD, FMN and also oxygen, heme, and tetrahydrobiopterin pyridine derivatives of niacin (BH4) → Both are converted to the oxidation-reduction coenzymes → Nitric oxide is a mediator in a broad array of biologic NAD+ and NADP systems ▪ They are electron acceptors or hydrogen donors in redox ▪ Potent vasodilator used for the treatment of angina or reactions and cellular respiration chest pain ▪ NAD+ is required for the poly-ADP-ribose polymerase ▪ Mechanism behind penile erection and is used as treatment reaction: regulates DNA replication, repair and cell progression → Note: Not the same with nicotine, as its pyridine ring is attached to either carboxyl group or amide group instead of a pyrrolidine ring. Role of NAD+ in redox reactions → In the citric acid cycle, there are reactions that require NAD+ as the acceptor of hydrogens → Four dehydrogenase enzymes that rely on NAD: pyruvate dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase → NAD+ is then reduced to NADH2 and donates the electrons to the ETC in the mitochondrion → Citric acid cycle will not proceed if vitamin B3 is not in the form of NAD+ and NADH = decreased ATP Production and weakness Figure 10. Role of FAD and FMN in Nitric Oxide Synthesis[Dr. Faustino’s PPT] Table 1. Other dehydrogenases that employ NAD+ or NADP+ as Other importance of Riboflavin: coenzymes → Required for iron mobilization NAD+ NADP+ ▪ Anemia (normocytic and normochromic type) is observed in Glutamate DH Glucose 6-PO4 DH Vitamin B2 deficiency Glyceraldehyde 3-PO4 DH Xylitol DH To check Riboflavin status: Lactate DH → Measure erythrocyte glutathione reductase activity Alcohol DH Special concern: UDP - glucose DH → Riboflavin is light sensitive D- xylulose DH → Newborns being treated for hyperbilirubinemia by phototherapy B-Hydroxyacyl DH is a concern because visible light decomposes Vit B2. Hence, Sorbitol DH these babies are at risk for riboflavin deficiency. Pyruvate DH RIBOFLAVIN: FOOD SOURCES Eggs Functions of Niacin Cereals → Participates in redox reactions Milk → Participates in cell respiration and DNA repair & replication Meat → Lowers LDL and TAG by inhibiting diacylglycerol transferase-2 ▪ Diacylglycerol transferase-2 is a liver enzyme needed in RIBOFLAVIN DEFICIENCY TAG synthesis Classic Symptoms include: → Elevates HDL cholesterol by inhibiting its removal from the → Dermatitis circulation → Cheilosis or angular stomatitis ▪ Helpful in treating patients with dyslipidemia → Glossitis Pharmacologic dose of nicotinic acid = 1.4g - 4g/ day ▪ Desquamation and purplish color of the tongue (magenta → Exercise caution when giving niacin as it can cause elevated tongue) liver enzymes, hyperuricemia and facial flushing Confined to the skin and the mucous membrane NIACIN: FOOD SOURCES Not associated with a major human disease because Vitamin B2 is efficiently conserved or recycled Meats However, deficiency states can still be seen in cases of Peanuts & other legumes malnutrition, poor population, chronic alcoholism, those in strict Enriched cereals vegetarian diets, and pregnant patients Whole grains → During pregnancy there is an increase demand of Vitamin B2 Milk Deficiency states are not just because of poor intake but it NIACIN DEFICIENCY may also be caused by states of higher demand such as in Borderline deficiency pregnancy → Glossitis (redness of the tongue) D. NIACIN (VITAMIN B3) Pellagra Niacin can be produced from tryptophan → Italian word for “rough skin” → Not a very efficient process → Affects the skin, GI tract, CNS → To make 1 mg of vitamin B3, 60 mg of tryptophan is needed → 3 Ds + Death → Vitamin B2, B6, and Fe2+ is also needed ▪ Dermatitis → Synthesis of niacin from tryptophan proceeds only after all − Casal’s necklace - increased pigmentation around the needs for tryptophan have been met neck → Hence, not a top priority − Cracked, scaly skins in sun exposed area Strictly speaking, vitamin B3 is NOT a vitamin since it can be ▪ Diarrhea synthesized by the body, but dietary intake of both tryptophan and ▪ Dementia niacin is recommended − Degeneration of nervous tissues In short, niacin is essential. ▪ Death → Needs to be supplied from the diet − Occurs if left untreated BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 4 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD PATHOLOGIC CONDITIONS ASSOCIATED WITH NIACIN PYRIDOXINE: METABOLIC FUNCTIONS DEFICIENCY Carbohydrate Metabolism Hartnup disease → Co-factor in glycogen degradation into glucose via glycogen → Pellagra develops despite an adequate intake of niacin phosphorylase → Result of a defect of the transport mechanism of Amino Acid Metabolism tryptophan leading to decreased reabsorption of niacin → Since vitamin B6 plays a role in amino acid metabolism, its Chronic alcoholism requirement increases with increased protein intake. → Decreased GIT absorption of niacin → Cofactor in transamination, condensation, decarboxylation, and Carcinoid syndrome deamination reactions. → GIT tumors that secrete serotonin, which is produced from ▪ Essential in transaminase reactions as it allows the tryptophan (depletes tryptophan) interconversion of amino acids and their entry into energy → Leads to depletion of tryptophan generating pathways. Other causes of niacin deficiency: ▪ In the figure below, the amino group from alanine was → B6 deficiency transferred to glutamate. The pyruvate that was produced → Isoniazid can be used in gluconeogenesis or enter in the TCA cycle. E. PANTOTHENIC ACID (VITAMIN B5) Integral component of Coenzyme A → Integral to energy production → E.g. Succinyl CoA, HMG CoA, Fatty acyl CoA, Acetyl CoA Other components: → β-mercaptoethylamine → Adenosine 3’-5’-diphosphate Figure 13. Alanine aminotransferase reaction[Dr. Faustino’s PPT] Figure 11. Coenzyme A[Dr. Faustino’s PPT] PANTOTHENIC ACID DEFICIENCY Not common because of widespread availability in natural foods → There is no evidence of Vitamin B5 deficiency in humans. Exceptions would be those in experimental diets. F. PYRIDOXINE (VITAMIN B6) Figure 14. Pyridoxal-phosphate-dependent reaction involving Glutamate decarboxylase[Devlin] Synthesis of Neurotransmitters → Co-factor in the synthesis of serotonin, melatonin, nor/epinephrine, dopamine, ɑ-aminobutyrate, histamine, sphingolipids, and sphingomyelin ▪ Deficiency can be seen as irritability, nervousness, and Figure 12. Structure of Pyridoxine[Dr. Faustino’s PPT] depression (low levels of serotonin) → Severe B6 deficiency manifests as peripheral neuropathy Pyridoxine is a collective term for 3 naturally occurring pyridine (tingling sensations in the extremities) and convulsions derivatives: ▪ The decarboxylation reaction of glutamate to GABA, an → Pyridoxine (alcohol) inhibitory neurotransmitter, via glutamate decarboxylase is → Pyridoxal (aldehyde) vitamin B6-dependent. Therefore, a deficiency of GABA → Pyridoxamine would cause neurologic symptoms like irritability and All three compounds serve as precursors of the biologically convulsion. active form, pyridoxal phosphate (PLP) → Production of sphingolipids and sphingomyelin → PLP is absorbed in the jejunum ▪ Sphingomyelin - myelin sheaths which are essential in the Pyridoxine is the major form of Vitamin B6 in the diet. CNS BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 5 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD Heme Synthesis → PLP is required in the synthesis of aminolevulinic acid (ALA) ▪ ALA - a precursor of heme, so deficiency can manifest as sideroblastic anemia (microcytic, hypochromic type) ▪ Synthesis of heme is vitamin B6-dependent, without heme iron cannot be used in the synthesis of hemoglobin. ▪ As a result, iron accumulates in the erythroblasts in the bone marrow (sideroblasts). Figure 17. Isoniazid and Pyridoxal complex[Dr. Faustino’s PPT] → Isoniazid forms a complex with Vitamin B6 forming an inactive hydrazone derivative. ▪ Used to treat TB and can induce vitamin B6 deficiency by Figure 15. Nucleated RBCs with iron granules[Dr. Faustino’s PPT] forming an inactive hydrazone derivative. → B6 is usually incorporated in most commercial preparations of Cysteine Synthesis from Homocysteine isoniazid → B6 is needed in converting homocysteine to cysteine → People who take oral contraceptive pills are advised to ▪ Vitamin B6 deficiency causes homocysteine to build-up in increase their vitamin B6 requirement (still an ongoing debate). the blood (homocysteinemia) = increased risk for Dermatologic (Pellagra-like) cardiovascular diseases (e.g., myocardial infarction) and → Similarities with B3 deficiency: pellagra-like symptoms since cognitive decline in the elderly pyridoxine affects tryptophan and niacin metabolism → Similarities with B2 deficiency: dermatitis, cheilosis, glossitis Neurologic → Weakness ▪ Due to decreased synthesis of serotonin and catecholamines ▪ Decreased glycogenolysis ▪ Anemia → Peripheral neuritis ▪ Due to decreased synthesis of sphingolipids = demyelination of nerves → Convulsions and coma ▪ Due to decreased synthesis of the neuroinhibitory GABA Hematologic → Sideroblastic anemia ▪ Microcytic, hypochromic type Figure 16. Synthesis of Cysteine from Homocysteine[Dr. Faustino’s PPT] G. BIOTIN (VITAMIN B7) PYRIDOXINE: FOOD SOURCES Meat: Beef, liver, fish, and poultry Vegetables Whole-grain cereals Egg yolk Fruits (except citrus fruits) PYRIDOXINE STATUS Can be measured using erythrocyte aspartate aminotransferase PYRIDOXINE: DEFICIENCY Seen in: → Chronic Alcoholism → Obesity → Malabsorption states (absorbed in jejunum) → End-stage renal disease → Autoimmune conditions (Crohn’s disease, Ulcerative colitis, Figure 18. Structure of BiotinDr. Faustino’s PPT] Celiac disease) Consists of: Isoniazid and Pyridoxine → Imidazole ring → Thiophene ring → Valeric acid side chain A prosthetic group of most ATP-dependent carboxylases: → Pyruvate carboxylase → Acetyl-CoA carboxylase Space intentionally left blank → Propionyl CoA carboxylase → β-methylcrotonyl CoA carboxylase Functions as a specialized carrier of one-carbon group → Other one-carbon group carriers: ▪ Folic acid ▪ S-adenosylmethionine (SAM) BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 6 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD ROLE OF BIOTIN IN CARBOXYLATION REACTIONS Conversion of Pyruvate to Oxaloacetate → The rate-limiting reaction of gluconeogenesis is a carboxylation reaction which is catalyzed by pyruvate carboxylase → Biotin attached to CO2 is needed as a source of carbon to form oxaloacetate → Biotin functions as a specialized carrier of one carbon group. Others are folic acid, and s-adenosylmethionine (SAM). Figure 19. Reaction catalyzed by pyruvate carboxylase using biotin [Dr. Faustino’s PPT] Conversion of Acetyl CoA to Malonyl CoA → Occurs in FA synthesis → Biotin acts as a one carbon donor in partnership with a carboxylase. Figure 21. Reaction catalyzed by propionyl CoA carboxylase using biotin[Dr. Faustino’s PPT] Figure 20. Reaction catalyzed by acetyl CoA carboxylase using biotin[Dr. Faustino’s PPT] Conversion of Propionyl CoA to D-Methyl Malonyl CoA → Occurs in heme synthesis → Biotin is the source of carbon group in the carboxylation of propionyl CoA ▪ The product succinyl CoA then enters CAC for energy synthesis or as a substrate in synthesis of porphyrin and heme Figure 22. Reaction catalyzed by β-methylcrotonyl CoA carboxylase using biotin[Dr. Faustino’s PPT] Catabolism of Leucine → Leucine becomes degraded into either acetoacetate or acetyl CoA via several reactions using biotin as a source of carbon group → Carboxylation of β-methylcrotonyl CoA to β-methylglutaconyl CoA, catalyzed by β-methylcrotonyl CoA carboxylase → Failure to catabolize leucine to acetoacetate and acetyl CoA Space intentionally left blank contributes to manifestations of biotin deficiency (weakness) BIOTIN: METABOLIC FUNCTIONS Energy producing reactions Lipid Metabolism → FA Synthesis: conversion of acetyl CoA to malonyl CoA via Acetyl CoA carboxylase → Heme Synthesis: conversion of propionyl CoA to succinyl CoA via Propionyl CoA carboxylase Carbohydrate Metabolism → Gluconeogenesis: carboxylation of pyruvate to OAA via Pyruvate carboxylase BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 7 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD Protein Metabolism → Depending on the carbon units attached to nitrogen 5 or → Leucine catabolism nitrogen 10, the folate derivatives can donate 1 carbon group ▪ β-methylcrotonyl CoA carboxylase (β-methylcrotonyl CoA to in different oxidation states to another molecule, depending on β-methylglutaconyl CoA) what the body needs. → Most reduced form: methyl BIOTIN: SOURCES → Most oxidized form: formyl Intestinal flora (synthesize biotin in excess of what we need) → Most versatile 1-carbon carriers because they can give Diet: carbon groups in different oxidation states depending on what → Whole grains, oatmeal the body needs. → Meat products (pork, chicken, fish, beef) → Peanuts, legumes MUST KNOW → Milk, chocolates 1 carbon carriers → Eggs → FH4 - primary in AA metabolism, donates methyl and formyl → S-AdenosylMethionine (SAM) - donates methyl groups BIOTIN: DEFICIENCY → Biotin - carries carboxyl groups / CO2 “Egg white injury” occurs when the diet consists greatly of raw egg white which contains avidin → Avidin from raw egg whites ▪ Great affinity to biotin ▪ Forms avidin-biotin complex → Avidin forms very stable complexes with vitamin B7 (Avidin-Biotin complex) ▪ Not attacked by digestive proteases = biotin cannot be absorbed Biotin deficiency is rare - since requirement is low TRIVIA Biotin was originally named Anti-Egg White Injury Factor or Vitamin H H. FOLIC ACID (VITAMIN B9) Folates Figure 24. Interconversion of folic acid derivatives[Devlin 7th ed] → Collective term for folic acid and its derivatives → Sounds like “Foliage” named for its presence mostly in green, Almost all of the reactions demonstrate bidirectional arrows which leafy vegetables especially spinach. means they are interconvertible (1-carbon/folate pool in orange Humans cannot synthesize their own folic acid, so we have to get box), EXCEPT for the conversion of N5,N10 it from our diet. methyleneH4folate to N5-methyl H4 folate which is Occurs in the diet as polyglutamate derivatives. unidirectional (red circle) → Once in the N5 methyl folate form, the only way to go is back to THF, which can only be done if Vitamin B12 is present (Methyl-folate trap) → Methyl-folate trap - the lack of Vitamin B12 will cause homocysteine to accumulate, equating to a higher risk for coronary artery disease. MUST KNOW Vit B6 is needed for the conversion of homocysteine to cysteine. Otherwise, you also have homocysteine buildup which is a risk for coronary artery disease. Cobalamin is also important in preventing the accumulation of homocysteine. Hence, Vitamins B6, B9, and B12 are important to prevent the accumulation of homocysteine. Folates are also needed to produce dTMP and purine rings, which are needed for DNA synthesis Other products: Serine, Glycine, and Methionine Figure 23. Folic Acid Structure[Devlin 7th ed] Folic acid also participates in amino acid metabolism. 3 major structural components: FOLIC ACID DEFICIENCY → Pteridine ring Macrocytic, megaloblastic anemia results from the combined → Para-aminobenzoic Acid (PABA) deficiency of Vitamins B9 & B12 (hematopoietic B vitamins). ▪ Required for the growth of many bacteria. When there is folate deficiency, there is impaired DNA → Polyglutamate tail replication, affecting rapidly dividing cells, particularly ▪ Made up of 3-8 glutamate residues bound by gamma hematopoietic cells. peptide links → Cells are arrested in the S phase of cell division. Therefore, Physiologically inactive there is synthesis of abnormally large but immature red → But once inside the cell, it is converted in the liver into its active blood cell precursors. form, tetrahydrofolate, by 2 successive reductions with the → Large = “macrocytic”, they are in the bone marrow = “blasts” help of the enzyme, dihydrofolate reductase. → Thus it is called, Macrocytic, megaloblastic anemia → Reduction is the favored direction of this reaction. → RBCs have fragile membranes which are easily destroyed. → Most of the folate in our body is present as tetrahydrofolate Hence, patients get anemia. (THF or FH4) → DNA synthesis is inhibited (no dTMP and purines) Tetrahydrofolate Non specific symptoms: loss of appetite, diarrhea, weakness → Active form of folic acid Folate status in the body is affected by our intake as well as our → Function: carrier of 1-carbon units in amino acid body’s capacity to absorb it metabolism. BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 8 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD → Groups of concern: alcoholics and elderly population due to impaired absorption. Certain drugs may also affect the availability and even the absorption of folic acid. → Eg. anticonvulsants and oral contraceptive pills A person may also have a relative deficiency during times of increased demand such as during pregnancy (preconception). → Folate is needed in DNA synthesis and fetal development involves continuous cell division. → A pregnant patient needs 600 micrograms of folic acid per day. Figure 27. Metabolism of 5-FU and MTX[Dr. Faustino’s PPT] 5-Fluorouracil → Anticancer drug → Pyrimidine-nucleotide analog (same structure as pyrimidines) → In the body, it is converted by salvage enzymes into dfUMP, Figure 25. Spina bifida in a newborn infant[Dr. Faustino’s PPT] which has a similar structure to dUMP. Myelomeningocele ▪ dfUMP competes with dUMP at the active site of → Severe form of spina bifida wherein a part of the baby’s thymidylate synthase spinal cord and nerves are contained in a sac that is seen ▪ dUMP cannot be converted to dTMP. through an opening in the back. → dTMP is not formed = NO DNA synthesis & cell division = NO → One of the many types of neural tube defects (defective tumor growth & proliferation of cancer cells development of the CNS) because of Folic Acid deficiency Methotrexate (MTX) during pre-pregnancy. → Another chemotherapy drug that is also an anti-metabolite. ▪ Folic acid is needed to minimize the chances of neural tube → To recycle dihydrofolate, it needs to undergo reduction to THF. defects in newborns. → Afterwards, it receives a carbon group to become N5, N10 → Folic Acid should be started prior to getting pregnant, methylene. since the neural tube closes as early as 6 weeks. → Methotrexate has the same structure as folates, making them ▪ By the time a woman discovers that she is pregnant, which synthetic analogs of folates. It competes with dihydrofolate at is around 6-8 weeks, the formation of the neural tube is the active site of dihydrofolate reductase. already done. ▪ Dihydrofolate cannot be reduced to THF. ▪ The time that a woman needs folic acid most is the time ▪ Rapidly dividing cells exhaust all their sources of THF. when she’s not yet aware that she is pregnant. ▪ When all stores are used up and not replenished, further ▪ Women of reproductive age and are having unprotected sex multiplication of the cancer cells stops because you do not and consequently can get pregnant anytime are advised to form FH4 which is necessary for continuing the cycle. take folic acid everyday. → Used in the treatment of leukemia, choriocarcinoma, other Anencephaly neoplastic diseases, rheumatoid arthritis, and psoriasis. → Skull doesn’t close; brain only covered by skin → In obstetrics, it is used in the medical management of ectopic pregnancies. Figure 26. Neonate with Anencephaly[Dr. Faustino’s PPT] FOLIC ACID: FOOD SOURCES Green, leafy vegetables Fruits (including citrus fruits) Folic-enriched cereals, grains Liver Yeast Figure 28. Comparison of the structures of Aminopterin and MTX[Dr. Faustino’s PPT] FOLIC ACID INHIBITORS Recall: dTMP is used for DNA synthesis Aminopterin → dTMP is produced from dUMP. In the synthesis of dTMP, N5, → A structural analog of folic acid which is identical to MTX N10 methylene tetrahydrofolate is needed to donate a carbon except for the methyl group at N10. group. → Also a competitive inhibitor of dihydrofolate reductase. → Also used in the treatment of certain cancers. BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 9 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD 1. Mitochondrial Synthesis of Succinyl CoA Vitamin B12 is a cofactor in the conversion of L-methylmalonyl CoA → Succinyl CoA enters the TCA cycle for energy synthesis Reaction is also essential in amino acid metabolism Route for fatty acids to enter energy synthesis. Decreased/absence of Vitamin B12 or methylmalonyl CoA = increased/accumulation of methylmalonyl CoA → methylmalonyl aciduria. Accumulation of L-methylmalonyl CoA = decreased de novo synthesis of FAs → irreversible demyelination → neurologic signs and symptoms Anemia is also observed because Succinyl CoA is needed in heme synthesis. Figure 29. Metabolism of Sulfonamides and Trimethoprim[Dr. Faustino’s PPT] Antibiotics → Recall: ▪ Most bacteria can synthesize their own folate. ▪ Folate is made up of pteridine, PABA, and glutamate tail. → Sulfonamides ▪ Structural analogs of PABA ▪ Instead of PABA, it inserts a sulfonamide between the pteridine and glutamate tail, so the bacteria cannot form folic acid leading to inhibited growth and proliferation of the bacteria → Bacteria do not die; growth/proliferation is inhibited. ▪ Bacteriostatic → Trimethoprim ▪ Inhibits bacterial dihydrofolate reductase, inhibiting synthesis of THF. ▪ Results to bacteria death, making it bactericidal. ​Figure 31. Cytoplasmic Synthesis of Methionine[Dr. Faustino’s PPT] → Cotrimoxazole (Bactrim®) 2. Cytoplasmic Synthesis of Methionine ▪ Combination of sulfamethoxazole and trimethoprim Conversion of homocysteine to methionine ▪ Antibiotic combo frequently used for treating UTI. Folate and Vit. B12 are required I. COBALAMIN (VITAMIN B12) Methionine is also essential in the synthesis of SAM. Contains a corrin ring system, which is similar to heme EXCEPT for the Cobalt in the center. COBALAMIN DEFICIENCY → It is Iron in heme. Intrinsic factor is needed for the absorption of cobalamin → Only known function of cobalt in the body, as part of Vit. B12 from the diet is usually protein-bound, released by either: cobalamin. → Protein hydrolysis in the stomach Has different coenzyme forms depending on what is attached to → Trypsin digestion in the intestines the central Cobalt After unbinding from protein, it combines with the intrinsic factor → Methyl = methylcobalamin and gets absorbed in the ileum. → Cyanide = Cyanocobalamin → 5’-deoxyadenosylcobalamin Synthesized solely by the GIT flora and is absent in all plants. → Strict vegans are at risk for Vitamin B12 deficiency. → Vegans, people with malabsorption problems (post-gastrectomy), and those who are not producing enough HCl are at risk. Concentrated in the livers and kidneys of animals Found in fish, dairy, and meat TWO METABOLIC ROLES OF COBALAMIN  ​Figure 32. Pernicious Anemia[Dr. Faustino’s PPT] ​Figure 30. Mitochondrial Synthesis of Succinyl CoA[Dr. Faustino’s PPT] BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 10 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD Pernicious Anemia O2 radical quencher (antioxidant) → Autoimmune destruction of the gastric parietal cells producing the intrinsic factor causing IF deficiency preventing the absorption of Vit. B12. 📋 → Along with Vit. A and E Mnemonic: Anti o-CE-dants → Scavenger of toxic reactive oxygen species (ROS): O2-, OH-, ▪ Uncomplexed Vit B12 can still be absorbed; but is H2O2, etc. inefficient & impractical → At physiologic pH, Vitamin C exists as enolate anion form, that → Patients undergoing surgical removal of the stomach due to acts as a reducing agent by donating H+ atoms to the ROS cancer or bariatric surgery may develop symptoms of that are formed during metabolic reactions pernicious anemia. → Vitamin C is then converted to a dehydroascorbyl radical, → Patients later on develop CNS symptoms due to progressive which is unreactive (resonant stabilized species) and does not demyelination of nerve cells because of decreased synthesis propagate radical damage. of fatty acids. → The action of dehydroascorbate reductase further degrades → Treatment: oral or intramuscular high dose Vit. B12 the radical into either ascorbate or dehydroascorbate (both are Megaloblastic Anemia not free radicals). → Methyl-Folate Trap: deficiency of Vit. B12 traps the folate in Coenzyme in hydroxylation reactions (carnitine synthesis, bile the N5-methyl form and will compromise the production of acid, collagen & catecholamine synthesis) & tyrosine purine ring and dTMP for DNA synthesis. degradation → Treatment: folate supplements Reducing agent ▪ Vitamin B12 deficiency will still be present and will still → Converts iron from the Fe3+ to the Fe2+ form (absorbed better) cause CNS symptoms due to demyelination (irreversible in the stomach process). Megadoses (>1gm/day) have no proven role in preventing common colds but reduce the duration and severity J. ASCORBIC ACID (VITAMIN C) → Megadoses can lead to oxalate kidney stones, in theory. → Upper limit of Vit. C intake: 2g/day ▪ Higher doses can lead to diarrhea Anti-effective ​Figure 33. Ascorbic Acid Synthesis [Dr. Faustino’s PPT] 📋 The sole non-B vitamin that is water-soluble The only glucose-derived vitamin ​Figure 35. Role of Vit. C in Hydroxylation Reactions[Dr. Faustino’s PPT] → Humans lack L-gulonolactone oxidase, hence we can’t Role of Vit. C in Hydroxylation Reactions produce our own ascorbic acid so it must be supplied in our → Plays a very important role in collagen synthesis (found in the diet. skin and skeletal muscles, including granulating wounds) Common sources are citrus fruits, tomatoes, and peppers. → Procollagen is non-hydroxylated. → Easily destroyed by oxygen, metal ions, heat and light. ▪ To form mature collagen, it needs to be hydroxylated to form → Overcooking and prolonged storage of fruits and vegetables mature collagen which requires hydroxylase enzyme and can destroy Vit. C. ascorbate as cofactor. FUNCTIONS OF ASCORBIC ACID → Ascorbate maintains iron in reduced state (Fe2+). ▪ Oxidized to dehydroascorbate in the presence of oxygen, iron, and alpha-ketoglutarate for the reaction to proceed. ▪ Alpha-ketogluterate is losing its carboxyl group and is becoming succinyl at the process. ​Figure 34. Antioxidant Activity of Ascorbic Acid[Dr. Faustino’s PPT] ​Figure 36. Role of Vit. C in Catecholamine Synthesis[Dr. Faustino’s PPT] BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 11 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD Role of Vit. C in Catecholamine Synthesis III. FAT-SOLUBLE VITAMINS → Synthesis of catecholamines (epinephrine and norepinephrine) A. GENERAL CHARACTERISTICS from tyrosine requires the enzyme dopamine-β-hydroxylase, Contain rings and aliphatic side chain which is ascorbate dependent. Digested and absorbed into the lymphatics Role of Vit. C in the Synthesis of Bile Acids May require transport proteins → Synthesis of Bile Acids is regulated at the level of cholesterol Associated with cells that contain fats 7-hydroxylase, which is also Vit. C dependent enzyme. → Hydrophobic → Important in absorption of fats Ample amounts stored in tissues (ex. liver & adipose tissue) Excreted in the stools → Water-soluble vitamins are excreted through the kidneys. Harder to absorb Diseases in liver, gallbladder, and inflammatory bowel diseases that lead to fat malabsorption may cause deficiency states of the fat soluble vitamins. Difficult to metabolize and are not easily excreted → May remain in the body for long periods, thereby toxicities occur often especially if consumed in large quantities. B. VITAMIN A (Retinoids) Active forms → Retinol → Retinal (Retinaldehyde) → Retinoic acid Vitamin A precursors are synthesized by plants as carotenoids ​Figure 37. Role of Vit. C in Tyrosine Degradation & Carnitine All dietary forms of vitamin A are converted into retinol Synthesis [Dr. Faustino’s PPT] → Primary alcohol with β-ionone ring and an isoprenoid chain of unsaturated fatty acids. Role of Vit. C in Tyrosine Degradation → Transport and storage form of Vitamin A. → Tyrosine from phenylalanine undergoes a series of reactions → From the small intestine, it is bound to retinol-binding protein that convert its carbon skeleton into either acetoacetate or for transport to the liver which can store a year’s supply of fumarate. The enzymes use Vitamin C as a cofactor. vitamin A. ▪ Deficiency of the enzyme para-hydroxyphenylpyruvate Conversion of carotenoids from plant sources to retinol is not dioxygenase results in neonatal tyrosinemia. 100% efficient − Benign condition in newborns Retinol Activity Equivalent (RAE) − Treatment: Dietary protein restriction and ascorbate → Vit. A potency of food is expressed as RAE supplements → 1 RAE = 1 ug retinol = 3.33 IU Role of Vit. C in Carnitine Synthesis ▪ 12 ug beta-carotene(most potent source) → Carnitine production is catalyzed by oxygenases that require ▪ 24 ug alpha-carotene vit C ▪ 24 ug beta-cryptoxanthin ▪ Carnitine serves to transport long chain fatty acids during the ꞵ- oxidation process β-CAROTENE ▪ With vitamin C deficiency, there’s a decreased rate of ꞵ- oxidation of fatty acids causing decreased rate of ATP synthesis that leads to fatigue in scurvy and vit C deficiency VITAMIN C DEFICIENCY Results to impaired collagen connective tissue function because collagen is its major component → Poor wound healing Osteoporosis → Organic bone matrix consists largely of collagen, not only ​Figure 38. β-Carotene [Dr. Faustino’s PPT] calcium Taken from yellow and orange fruits and vegetables (chiefly Capillary Fragility carrots) → Collagen is a major component of the ground substance of Very effective antioxidant capillary walls → Reduces risks of cancer that are initiated by free radicals → Results to easy bruising, petechial hemorrhages in the skin and mucous membranes Anemia → Due to impaired intestinal iron absorption Scurvy → Due to defective hydroxylation of collagen → Capillary fragility → Muscle weakness → Soft, swollen, easy to bleed gums → Loosening of teeth → Poor wound healing → Anemia → Fatigue, malaise, depression → Bone demineralization ​Figure 39. β-Carotene metabolism[Dr. Faustino’s PPT] BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 12 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD VITAMIN A SYNTHESIS → The trans form is isomerized to 11-cis-retinal In the small intestine, β-Carotene is cleaved in carbons 14 and 15 by β-Carotene dioxygenase. → This reaction will yield 2 molecules of retinal that participate in the visual cycle. Retinal will undergo further metabolism in the intestine to produce retinol and retinoic acid then will be transported in the liver for storage. ​Figure 42. Summary of the visual cycle [Dr. Faustino’s PPT] NOTE Vitamin A is essential for vision Night blindness is an early symptom of vitamin A deficiency ROLE IN GLYCOPROTEIN SYNTHESIS Retinyl phosphate (glycoprotein synthesis) Glycoprotein is needed in the production of mucus → For the maintenance of healthy epithelial tissues ​Figure 40. Vitamin A synthesis [Dr. Faustino’s PPT] → Mucus has antioxidant effect Deficiency of Vit. A results in decreased mucus production ISOMERS OF RETINAL leading to drying of the epithelial tissues (e.g., respiratory tract, GI Retinal (visual cycle) tract, and genitourinary tract). → Isomers of retinal → When epithelial tissues are keratinized due to lack of mucus, 11-cis-retinal (dark-state) or vitamin A2 they become easily fissured. – Inactive form → Allows entry of microorganisms – Present in rods and cones of the retina in the dark state → Prone to infections and certain cancers – With light, 11-cis turns into 11-trans 11-trans-retinal (light-state) or vitamin A1 RETINOIC ACID (STEROID HORMONE) – Most common form Binds to: – Active form → RAR: Retinoic acid receptors – Present in rods and cones of the retina in the light state → RXR: Retinoid X receptors – It is the photoisomerization product of 11-cis-retinal in the ▪ These can bind to DNA and is involved in regulating cell dark and enzymes, 11-trans turns into 11-cis. growth and differentiation – Metarhodopsin II (all-trans retinal) active Vitamin A is considered a hormone TIP Light rail TRANSit (LRT) System ❗️ → Vitamins A and D have steroid activity Important in embryonic development and organogenesis Table 2. Summary of the Actions of Retinoids VITAMIN FORM FUNCTION Retinol Maintenance of reproduction; Hormonal down-regulates keratin synthesis → healthy epithelial tissue; Synthesis of transferrin (iron transport protein) Regulation of cell growth B-carotene → Retinal For vision Maintenance of reproduction ​Figure 41. Isomerization of retinal [Dr. Faustino’s PPT] Retinoic acid Hormonal down-regulates keratin SUMMARY OF THE VISUAL CYCLE synthesis → maintenance of healthy epithelial tissue; 📋 11-cis retinal + opsin = rhodopsin (visual pigment) Opsonin is found in the membranes of the photoreceptor (rods and cones) in the retina Synthesis of transferrin; Regulation of cell growth and of gene expression; In the presence of light, 11-cis-retinal is isomerized to Active ingredient in tretinoin for 11-trans-retinal treatment of severe acne and → There is a series of rapid geometric transformations to form wrinkled skin. metarhodopsin II (Active form of all-trans retinal). → Metarhodopsin II will activate the G-proteins called transducin Retinol phosphate Normal growth regulation; ▪ This will generate a rapid cascade of complex reactions Synthesis of glycoprotein for resulting in the generation of nerve impulses to the occipital mucus secretion. lobe (visual center of the brain) via the optic nerve for proper interpretation. → The opsin and trans-retinal will dissociate from each other → Regeneration of rhodopsin requires isomerization of all trans-retinal back to 11-cis-retinal. BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 13 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD 📋 →Vitamin A is not just for vision Retinol: synthesis of transferrin VITAMIN A EXCESS → Retinoic acid: active ingredient in Tretinoin for treatment of Because the fat-soluble vitamins are stored in the body and we severe acne & wrinkled skin; Isotretinoin being prescribed cannot easily get rid of them, there is always a danger of excess levels (along with toxicity). VITAMIN A DEFICIENCY STATES → 25,000 to 50,000 g/day vitamin A Vitamin A deficiency is rare in general population Vitamin A and Vitamin D Some populations are more prone such as those with: → Fat-soluble vitamins that can be toxic in excess → Severe liver damage (Retinol is stored in the liver) → With a normal diet, it is impossible to get excess in vitamin A → Diseases that cause fat malabsorption unless you consume massive vitamin A supplements. VITAMIN A DEFICIENCY MANIFESTATIONS ▪ Each capsule of Vitamin A usually has 4,500ug ▪ There is a limited capacity to store vitamin A in the body, Xerophthalmia prolonged excessive vitamin A intake over months or years Bitot’s spots may results in toxicity Keratomalacia Signs of Vitamin A Excess Night Blindness → Bone & joint pain → Xerophthalmia, Bitot’s spots, Keratomalacia, and night → Double vision blindness are manifestations related to visual cycle. → Scaly dermatitis & hair loss Anemia → Enlarged liver & spleen Decreased resistance to infection → Nausea, diarrhea Susceptibility to cancer → Teratogenic Mental and physical growth retardation because vitamin A ▪ Excess vitamin A in pregnant women participates in embryonic development, gene expression, and ▪ Cause malformations in the fetus (can also be seen in organogenesis. inadequate intake of vitamin A SEVERE DEFICIENCY MANIFESTATIONS COMMON SOURCES OF VITAMIN A Xerophthalmia Recommended intake: 600-900 mcg (different for age/gender) → Can lead to corneal ulceration and blindness Beta-carotene sources: → Due to the excessive keratinization of epithelial cells of the → Dark green vegetables lining of the eyes → Yellow vegetables → Progressive xerophthalmia can lead to softening of the cornea → Tomatoes or degeneration of corneal epithelium (causing corneal opacity) Preformed retinol/retinoic acid sources: leading to blindness. → Liver Bitot’s Spots → Fish oil → Dry, silver-gray plaques on the bulbar conjunctiva → Egg yolk → Due to keratinization of the epithelium of the conjunctiva → Butter and milk C. VITAMIN D AND CALCIUM Function of vitamin D → Important in Ca2+ homeostasis → Not a vitamin but a prohormone that is converted to a substance that acts like a steroid hormone. 2 sources: → Diet → Synthesized by 7-dehydrocholesterol (cholesterol precursor in the skin) VITAMIN D SYNTHESIS Synthesized by 7-dehydrocholesterol → Cholesterol precursor in the skin → Provitamin D3 in the Malpighian layer of the epidermis of the skin → Photolyzed into previtamin D3; (cis isomer) by UV light from the sun ​Figure 43. Severe Vitamin A deficiency manifestation [Dr. Faustino’s PPT] ▪ Reason why Vitamin D is called the sunshine vitamin − Conversion does not require any enzymes (UV light only) Hyperkeratosis ▪ Adequate sunlight is enough for vitamin D requirements → Retinol and retinoic acid also serve to downregulate keratin → Little to no dietary requirement for vitamin D compared to other synthesis. fat-soluble vitamins. → In the absence of retinol and retinoic acid, keratinized → Irradiation from the sun cleaves the carbon-carbon bond at epithelium will replace moist surfaces with scaly skin. C9-C10, opening the beta-ring to produce Previtamin D3. → Aside from dry scaly skin, follicular hyperkeratosis can also develop (like chicken). Previtamin D3 → The cis isomer is now isomerized to Cholecalciferol (vitamin D3 ▪ Trans isomer ▪ Most abundant form ▪ Takes place in the dermal and epidermal layers of the skin → Still in inactive form Vitamin D3 moves to the blood and is converted to its active form 1,25-dihydroxycholecalciferol via two sequential hydroxylation reactions in two organs. → 1st hydroxylation reaction occurs in the liver ​Figure 44. Hyperkeratosis [Dr. Faustino’s PPT] BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 14 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD ▪ It occurs at the C25 position in the presence of cytochrome o *Instead of active form (calcitriol) formation, there is P450, O2, and NADPH as cofactors, and catalyzed by synthesis of inactive form 25-hydroxylase (24,45-hydroxycholecalciferol) ▪ What is formed is 25-hydroxycholecalciferol (calcidiol or calcifediol) ▪ It is called calcidiol because of the presence of 2 OH groups at C3 & C25 ▪ This is the predominant form (storage form) of vitamin D in the plasma. → Major circulating form of the vitamin D but still inactive form [Dr. Faustino’s Figure 47. Increased PTH release due to low serum Ca2+ PPT] ​Figure 45. 1st Hydroxylation Reaction in the Liver (via 25-hydroxylase) [Dr. Faustino’s PPT] → 2nd hydroxylation reaction takes place mainly in the renal proximal convoluted tubules (PCT). ▪ Occurs in the C1 position ▪ Catalyzed by 1-α-hydroxylase in the presence of cytochrome P450, O2, and NADPH ▪ Product formed is 1, 25-Dihydroxycholecalciferol (calcitriol) − It is called calcitriol because of the presence of 3 OH groups at C1, C3 & C25 ▪ Calcitriol is the most biologically active form and also the most potent vitamin D (100x more potent than calcidiol) ▪ 2nd hydroxylation reactions can occur in the brain, pancreas, and colon (minor contribution and act on themselves). [Dr. Faustino’s Figure 48. Inhibited PTH release due to high serum Ca2+ PPT] CALCIUM Ca2+ homeostasis occurs because there is need to maintain serum Ca2+ levels within a relatively narrow range that is compatible with life Most abundant mineral in the body Functions → Works with enzymes and hormones → Blood coagulation → Muscle contractility → Normal neuromuscular irritability Figure 46. 2nd Hydroxylation Reaction in the Kidney (via 1-alpha-hydroxylase) [Dr. Faustino’s PPT] 💬 Either in your bones (majority) or outside of your bones When Ca2+ intake is not enough to maintain serum Ca2+ levels within normal, the bones are compromised because this → 2nd renal hydroxylation (kidney) is the major control point results in a net loss of Ca2+ from the bones which serves as in the active Vitamin D synthesis ▪ Stimulated or inhibited by PTH 💬 your reservoir Ages 10 to 35 is the best time to build up your Ca2+ stores as − Low serum Ca2+ → increased PTH release → increased 1-alpha-hydroxylase activity → increased calcitriol synthesis → increased serum Ca2+ 💬 this is the time you get maximum bone density Adequate Ca2+ intake and exercise should be done to avoid osteoporosis during old age − High serum Ca2+ → inhibited PTH release → ▪ Women: 1 gram of Ca2+ per day decreased 1-alpha-hydroxylase activity → decreased − Equivalent to 3 or more glasses of milk calcitriol synthesis* → decreased serum Ca2+ ▪ Get enough Ca2+ to build your stores and to meet your daily needs BIOCHEMISTRY Vitamins, Minerals, & Trace Elements PAGE 15 of 31 BIOCHEMISTRY | LE 1 Vitamins, Minerals, & Trace Elements | Karen M. Faustino, MD CALCIUM HOMEOSTASIS Figure 51. Response to low Vitamin D [Devlin, 5e] Much like Ca2+ deficiency, causes net demineralization of bones Body releases PTH Figure 49. Response to Low Plasma Ca2+ [Lippincott, 5e] → Stimulates bone resorption (Ca2+ moves from bones to blood) Vitamin D is a hypercalcemic hormone → Decrease rena