MMD FINAL EXAM OUTLINE.docx

38. Consider the two groupings of vitamins (water soluble and fat soluble). Water soluble ○ Water-soluble vitamins and/or their derivatives function as coenzymes for enzymes involved in metabolic pathways ○ Water-soluble vitamins – B complex and C Fat soluble ○ Some fat-soluble vitamins funct...

38. Consider the two groupings of vitamins (water soluble and fat soluble). Water soluble ○ Water-soluble vitamins and/or their derivatives function as coenzymes for enzymes involved in metabolic pathways ○ Water-soluble vitamins – B complex and C Fat soluble ○ Some fat-soluble vitamins function as hormones, some as anti-oxidants ○ Fat-soluble vitamins – A, D, E, and K ○ These vitamins are associated with lipids of the diet ○ Absorption of these vitamins requires the normal lipid absorption mechanisms, including emulsification by bile, normal mucosal cells, and transport in chylomicrons ○ These vitamins are stored in the body in the liver and adipose tissue 39. What are some of the physiological significances of vitamins? Water Soluble Vitamins Thiamine (B1) ○ The coenzyme form is thiamine pyrophosphate (TPP), which is involved in reactions of energy production ○ TPP is a coenzyme for pyruvate dehydrogenase (pyruvate → acetyl CoA) and for a TCA cycle enzyme ● Riboflavin (B2) ○ Riboflavin is a constituent of the coenzymes FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide) ○ These coenzymes function as electron carriers for oxidoreductases ○ Deficiency thereof is not associated with a major human disease Niacin (Nicotinic Acid) (B3) ○ Niacin is a constituent of the coenzymes NAD+ (nicotinamide adenine dinucleotide) and NADP+ (nicotinamide adenine dinucleotide phosphate) ○ These coenzymes function as electron carriers for oxidoreductases ○ Some niacin can be synthesized endogenously from tryptophan--an essential amino acid Pyridoxine (Vitamin B6) ○ The coenzyme form is pyridoxal phosphate (PLP) ○ This coenzyme is required by enzymes involved in amino acid metabolism, such as transaminases ○ In the 1960’s, when infants were fed a formula lacking this vitamin, they developed seizures and hyperirritability ■ Why? Pyridoxal phosphate is a cofactor involved with the enzyme glutamic acid decarboxylase (GAD), which converts glutamic acid to GABA ○ Isoniazid, used in the treatment of TB, can produce a B6 deficiency. ■ How? ■ Its metabolites directly attach to and inactivate pyridoxine species ■ Second, it directly inhibits the enzyme pyridoxine phosphokinase: ■ This enzyme activates pyridoxine to pyridoxal 5' phosphate--the cofactor in many "pyridoxine-dependent" reactions Folic Acid (B9) ○ The coenzyme form is tetrahydrofolate (FH4) and derivatives ○ FH4 functions as a carrier of 1-carbon groups for enzymes catalyzing 1-C transfer reactions ○ Tetrahydrofolate derivatives are required for nucleotide synthesis and for synthesis of methionine from homocysteine Vitamin B12 (Cobalamin) ○ The coenzyme forms are methylcobalamin and deoxyadenosylcobalamin ○ A reaction that requires B12 is the conversion of homocysteine to methionine ○ Intestinal absorption of B12 requires a glycoprotein called intrinsic factor (IF), which is synthesized in the parietal cells of the stomach ○ Large amounts of B12 are stored in the liver Vitamin C (Ascorbate) ○ Ascorbate is a coenzyme in the hydroxylation of proline and lysine residues in collagen, reactions that are required in the production of mature collagen ○ Vitamin C is also an anti-oxidant (reducing agent) ○ Vitamin C deficiency causes scurvy, which is characterized by bleeding gums, loose teeth, fragile blood vessels, impaired wound healing Fat Soluble Vitamins Vitamin A ○ Vitamin A has 3 active forms – retinol, retinal and retinoic acid ○ Function: ■ Important in growth, reproduction, immunity and cell differentiation ■ Help maintain healthy bones, skin and mucous membrane ■ Visual cycle as a constituent of the visual pigment--rhodopsin ○ β-carotene from plants is provitamin A – it is converted in the GI tract to retinal ○ β-carotene functions as an antioxidant ○ Animal sources provide vitamin A in the form of retinol and retinyl esters ○ They are absorbed and incorporated into chylomicrons ○ Stored in the liver as retinyl esters to the tissue ○ Delivered to tissue by retinol-binding protein (RBP) ○ Once delivered to the cell the cell will convert retinol to retinal or retinoic acid ○ In vision, retinol is carried to the retina and converted to retinal. It then combines with a protein opsin to form a pigment known as rhodopsin. It is an integral part of the visual cycle allowing us to see ○ Retinoic acid affects gene expression. It acts like a steroid hormone, binding to retinoid nuclear receptors, and enhancing transcription of certain genes involved in differentiation of stem cell into various cell types ○ Both retinol and retinal support sperm production and fertility ○ All forms of Vitamin A are essential for proper bone growth Vitamin D ○ Vitamin D3, cholecalciferol, is from animals (skin UV radiation) ○ Vitamin D2, ergocalciferol, is from yeast ○ The active form of the vitamin is 1,25-dihydroxycholecalciferol, or calcitriol ○ Function: ■ Calcitriol functions in calcium homeostasis primarily (Calcitriol: enhances the absorption of calcium and phosphorus from the small intestines and with PTH stimulates osteoclasts to break down bone and release calcium) ■ Also regulates cell differentiation and growth ○ Calcitriol functions like a steroid hormone in intestinal mucosal cells, binding to a cytosolic receptor and inducing the synthesis of a calcium binding protein ○ Vitamin D regulation of blood calcium ■ Ultraviolet light causes a form of Cholesterol to be converted to an inactive form of vitamin D cholecalciferol ■ The liver then converts to 25-hydroxycholecalciferol (calcidiol) ■ Through the action of PTH the kidneys convert calcidiol to the active form of Vitamin D (calcitriol) ■ Vitamin E Also called α-tocopherol ○ Normally, free radicals are produced to remove unwanted molecules ○ Functions as an antioxidant in the blood (LDLs) and in membranes ○ It protects membrane phospholipids from attack by reactive oxygen species (ROS) Vitamin K Vitamin K is required for the post-translational modification of coagulation factors II (prothrombin), VII, IX, and X ○ This reaction entails the conversion of glutamate residues on the proteins to γ-carboxyglutamate residues by carboxylation ○ γ-carboxyglutamate residues of prothrombin are strong chelators of Ca++, a necessary function in the conversion of prothrombin to thrombin in the coagulation cascade ● 40. Which hormones are known antioxidants? Melatonin, glucagon, insulin, estrogens, and progesterone?? Vitamins that are hormone like & Antioxidants: Vitamin A (B-carotene) , Vitamin E Be familiar with deficiencies of vitamins and the physiological impact thereof. Thiamine deficiency ○ Severe deficiency disease is beriberi: characterized by neurological disorders, paralysis, palpitations, cardiomyopathy, muscle atrophy and weakness, loss of weight ○ Inhibition of glutamate production and Gamma-aminobutyric acid GABA due to inhibition of the TCA cycle ○ Severe thiamine deficiency is called Wernicke-Korsakoff syndrome, or Wernicke encephalopathy ○ This is characterized by eye muscle weakness, poor muscular coordination (ataxia), loss of memory (amnesia) ○ Commonly observed in chronic alcoholism ○ If not treated, it can lead to coma and death Niacin deficiency ○ Niacin deficiency disease is pellagra, characterized by dermatitis, dementia, and diarrhea (the three Ds) ○ Niacin deficiency is also related to ingestion of an unbalanced amino acid mixture containing inadequate tryptophan Folate deficiency ○ A folate deficiency leads to decreased availability of nucleotides, which will lead to impaired DNA synthesis and cell division ○ This impairment in hematopoietic cells accounts for the signs and symptoms of megaloblastic anemia ○ During the first few weeks of fetal development will lead to neural tube defects (spina bifida) ○ Megaloblastic anemia is a bone marrow disorder in which normal maturation of rbc’s is impaired, leading to low hemoglobin levels and a high number of megaloblastic cells in the bone marrow ○ The red blood cells are macrocytic with fragile membranes ○ A folate deficiency also causes homocysteinemia, because FH4 derivative is required to convert homocysteine to methionine B12 deficiency ○ The most common disease of B12 deficiency is the disease known pernicious anemia (chronic atrophic gastritis) ○ Pernicious anemia is caused by an autoimmune disease wherein there is autoimmune destruction of the parietal cells of the stomach ○ Lack of IF(intrinsic factor) to B12 deficiency ○ Symptoms include megaloblastic anemia and irreversible degeneration of the spinal cord ○ Folate recycling is impaired ○ Neurological manifestations include paresthesias, difficulty in balance, spastic gait, and dementia Vitamin C deficiency ○ Caused by a deficiency of dietary vitamin C associated with malnutrition ○ Ascorbic acid involved in a variety of biosynthetic pathways ○ Synthesis of collagen, ascorbic acid is a cofactor for 2 enzymes: prolyl hydroxylase and lysyl hydroxylase ○ Two enzymes involved in hydroxylation of the proline and lysine amino acids in collagen ○ Hydroxyproline and hydroxylysine are important for stabilizing collagen by cross-linking in collagen Vitamin A deficiency ○ Early symptom is night blindness. This is due to inefficient regeneration of rhodopsin ○ Other symptoms include keratinization of epithelium and lack of mucus secretions; susceptibility to infections; drying and keratinization of the cornea (xerophthalmia) causing permanent blindness ○ There are pharmacological uses for retinoic acids in the treatment of acne and psoriasis ○ Accutane and Retin-A are forms of retinoic acid Vitamin D deficiency ○ Rickets, in children, entails improper mineralization of developing bone with resultant formation of weakened, soft pliable bones. Bowing of the legs ○ Osteomalacia, in adults, entails demineralization of existing bone, which causes bone to become soft and susceptible to fractures in the hip, spine and other bones ○ Osteoporosis, porous bones, is a condition of declining bone quality that impacts millions of Americans. It is progressive of both decline in bone density and strength Vitamin K deficiency ○ Vitamin K deficiency is associated with bleeding disorders. Vitamin K deficiency leads to hypoprothrombinemia ○ Vitamin K deficiency is common in newborns, leading to hemorrhagic disease of the newborn ○ Vitamin K antagonists are used therapeutically as anti-coagulants to treat thromboembolytic disease. Examples are dicumarol and warfarin. What is the importance of vitamin K in thrombosis? Vitamin K is required for the post-translational modification of coagulation factors II (prothrombin), VII, IX, and X This reaction entails the conversion of glutamate residues on the proteins to γ-carboxyglutamate residues by carboxylation γ-carboxyglutamate residues of prothrombin are strong chelators of Ca++, a necessary function in the conversion of prothrombin to thrombin in the coagulation cascade Vitamin K antagonists are used therapeutically as anti-coagulants to treat thromboembolytic disease. Examples are dicumarol and warfarin 43. Be familiar with the twin cycle hypothesis in the progressive development of Type II diabetes. Research has demonstrated that fatty liver and insulin resistance are lead-up to the development of diabetes Excess calories Fatty liver leads to fatty pancreas Dysfunction of both organs ○ Hepatic insulin resistance ○ Pancreatic-dysfunction Obesity Excess consumption + genetic component Adipocytes are larger (hypertrophy) and more numerous (hyperplasia) Metabolic syndrome includes glucose intolerance, insulin resistance, hyperinsulinemia, elevated plasma triacylglycerol, hypertension, chronic inflammation BMI BMI is weight/height2 (kg/m2) Normal BMI is 19-24.9 Below 19 is underweight Above 25 is overweight Over 30 is obese Greater than 40 is morbidly obese The Distribution of Body Fat is Associated with Health Risk Waist/hip ratio >0.8 in women and >1.0 for men ○ Upper body obesity Waist/hip ratio <0.8 in women and <1.0 for men ○ Lower body obesity Excess visceral and abdominal subq (in upper body) fat stores is observed with increase health issues associated with obesity. Since the pear shape has been shown to be protective, clinicians use the body shape in those who may be at higher risk for metabolic diseases