B vitamins Flashcards
- What are the four forms of thiamin, which have activity? What is the active part of the vitamin?
a. The four forms of thiamin are the free vitamin, mono, di (pyro) and tri phosphorylated forms. The free vitamin is non-active and thiamin pyrophosphate (TPP) is the major active form. Triphosphate (TTP) form has limited activity and monophosphate (TMP) form is an inactive metabolite of thiamin pyrophosphate.
b. The active part of TPP is carbon #2 (Between N and S) on the thiazole ring. This carbon is more acidic than most CH bonds and is capable of deprotonizing to form a carbanion. The carbanion is stabilized by N+ which allows it to attack carbonyl groups on alphaketo acids and ketoses. This conversion primarily happens in liver, kidney, RBC, and brain as well as other tissues by thiamin pyrophsophokinase with ATP providing the pyrophosphate group.
c. 80% of thiamin present in the body is TPP, 10% is TTP and the rest as TMP and free thiamin
- What is the major mechanism of absorption; be able to explain the role of alcohol and thiaminases in digestion and absorption.
a. About 80% of thiamin is absorbed. Prior to absorption, the free form is dephosphorylated. It is absorbed by Na-dependent active transport at normal dietary intakes and by passive diffusion or paracellularly when dietary intake is increased. Absoprtion happens in the small intenstine with the most being in the jejunum.
b. Unique to thiamin is ethanol-inhibition of the active transport system in the basolateral membrane. Thus, alcoholics are susceptible to thiamin deficiency,
- What are the three major functions of thiamin, which form is responsible for each function?
a. Oxidative decarboxylation of alpha-keto acids in energy metabolism
i. The first enzyme in alpha-keto acid dehydrogenase complexes is the alpha-keto decarboxylase, in which TPP acts as the coenzyme in the decarboxylation reaction producing an acyl group and CO2.
b. 2 carbon transfers in the non-oxidative branch of the hexose monophosphate pathway
i. TPP is an important coenzyme in transketolase dependent reactions in the non-oxidative branch of the hexose monophosphate pathway.
c. Membrane transduction in nerve conduction
i. TTP or TPP occupies a site at or near Na-channels and the dephosphorylation of thiamin phosphoesters opens these Na-channels allowing depolarization of the cell membrane, with the subsequent conduction of a nerve impulse down the nerve fiber.
- Be able to explain -keto acids dehydrogenases (how thiamin, riboflavin, niacin, pantothenic acid, and lipoic acid are all involved)
a. The first enzyme in alpha-keto acid dehydrogenase complexes is the alpha-keto decarboxylase, in which TPP acts as the coenzyme in the decarboxylation reaction producing an acyl group and CO2.
b. Lipoic acid and pantothenic acid (CoA)
- Explain the role of thiamin in the HMP.
a. TPP is an important coenzyme in transketolase dependent reactions in the non-oxidative branch of the hexose monophosphate pathway. TPP forms a carbanion which attacks the carbonyl group of ketoses and transfers 2-carbon unit to an aldose acceptor
- What is the major deficiency disease for thiamin; be familiar with alcohol-related thiamin deficiency
a. Beriberi is the disease associated with deficiency: Wet, dry and acute
i. Wet
1. Involves extensive cardiovascular complications including the right side cardiac failure, pulmonary and generalized edema and neurological involvement
ii. Dry
1. Long term deficiency usually in elderly population
iii. Acute
1. Appears most often in children and young adults and has a rapid onset and may result from acute severe deficiency in rapidly growing children and young adults
b. Thiamin deficiency has also been associated with Wernicke-Korsakoff syndrome described in individuals with chronic alcoholism. Alcoholism often results in thiamin deficiencies for several reasons. First alcoholics have deficient or diminished micronutrient intake. Secondly alcohol interferes with the Na-dependent active transport of thiamin across the basolateral membrane, thus limiting absorption of what little thiamin may be in their diets. Finally, chronic alcoholism is also associated with liver disease, thus compromises the ability of the liver to form the active forms of the vitamin.
- What is the vitamin form of riboflavin, and what are the two active forms of the vitamin?
a. The free vitamin riboflavin consists of a flavin moiety attached to the sugar alcohol ribitol.
b. The 2 active forms are flavin mononucleotide (FMN), the phosphoester of the free vitamin and flavin adenine dinucleotide (FAD) in which AMP is attached to FMN
- In what form is riboflavin found in foods, what form is absorbed, and what is the mechanism of absorption?
a. Riboflavin is found mostly in milk, dairy products, eggs and meats
b. Riboflavin is found in foods as free riboflavin bound to protein and as its two coenzymes FMN(H2) and FAD(H2)
c. Most riboflavin is noncovalently bound to protein and can be hydrolyzed by HCL in the stomach to free riboflavin. FAD is more intimately bound to proteins and must be freed by proteases in the stomach and small intestine. In the small intestine, FAD is converted to FMN by FAD pyrophosphatase and then to free riboflavin by FMN phosphatase.
- What is the major mechanism of riboflavin’s activity; be able to provide a few examples of major enzyme systems that it is involved in as a vitamin.
a. Riboflavin is in a wide variety of oxidation reduction reactions within cells and exist in two states – oxidized (FMN and FAD) and reduced (FMNH2 and FADH2)
b. Examples of major enzyme systems that it is involved in
i. Krebs cycle – succinate dehydrogenase
ii. Electron transport chain – NADP dehydrogenase
iii. Oxidative decarboxylation of alpha keto acid – Pyruvate dehydrogenase
- Be able to describe the relationship between riboflavin and niacin; how does it interact with other vitamins; what vitamins may be affected by riboflavin deficiency?
a. Since riboflavin functions as a prosthetic group within the active site of enzymes, it is unable to regenerate its active form and therefore relies on niacin coenzymes to enter the active site and regenerate the active coenzyme form of riboflavin
- What are the two vitamin forms of niacin; what are the two major forms of the active vitamin; how do they differ in function?
a. Two vitamin forms are nicotinic acid and nicotinamide
b. Two major forms of the active vitamins are nicotinamide adenine dinucloetides (NAD+/NADH) and nicotinamide adenine dinucleotide phosphate (NADP+/NADPH)
c. The major function of NAD)H) coenzymes is in oxidation-reduction reactions, many of which are dehydrogenases or reductases important in energy metabolism
d. The major function of NADP(H) are involved in reductive biosynthetic reactions such as the synthesis of fatty acids, cholesterol and steroid hormones as well as in antioxidant defense systems
- Be able to describe the dietary sources of niacin. How did this relate to the development of niacin deficiency in the US and Central Europe but not in the southwest U.S. and Mexico; why is corn a particularly poor source on niacin?
a. Niacin is found in a variety of foods of both animal and plant sources primarily as NAD(H) and NADP(H)
b. Good sources include fish, meats, legumes, nuts, teas and coffee and enriched grains.
c. Corn is a poor source of preformed niacin unless treated with limewater such as is the case in Southwest US, Mexico and Central America. It is also a poor source of the amino acid tryptophan which is a direct precursor of niacin synthesis in the liver
- How is niacin absorbed?
a. Niacin is hydrolyzed to NMN by non-specific pyrophosphatases, phophatases and glycohydrolases within the GI tract.
b. Nicotinic acid but not amide can be absorbed by passive diffusion across the gastric mucosa. However, most of nicotinic acid and nicotinamide are absorbed in the small intestine through facilitated transport.
- Be able to provide examples of a few major enzymes systems that used niacin as a coenzyme. What is it proposed non-coenzyme role; what is its pharmacological (non-vitamin) role, which form is important in this role?
a. Examples of few major enzyme systems NAD(H)
i. Glycolysis – glyceraldehydes 3 phosphate dehydrogenase
ii. Oxidative decarboxylation of alpha keto acid – pyruvate dehydrogenase
iii. Krebs cycle – pyruvate dehydrogenase
iv. Electron transport chain – NADH dehydrogenase
b. Examples of few major enzyme systems (NADP(H)
i. Cholesterol synthesis – HMG CoA reductase
ii. Fatty acid synthesis – Beta-ketoacyl ACP reductase
iii. Hexose monophosphate pathway – gluce 6 phosphate dehydrogenase
iv. Ketone metabolism – Beta-hydroxybutyate reductase
c. Non-coenzyme role
i. NAD as a substrate for glycohydrolases yielding nicotinamide and an ADP ribosyl moiety (ADPR). The ADPR is then conjugated to acceptor proteins to form ADP ribosylated proteins. ADPR have been shown to function in DNA replication and repair as well as cellular differentiation
d. Pharmaceutical role
i. Only nicotinic acid and not nicotinamide demonstrates pharmacological activity at doses between 1.5 – 3.0 grams. It is used to lower triaglycerol and cholesterol concentrations in individuals with combined hyperlipoproteinemia and has been shown to be helpful in lowering VLDL-TG and thus LDL-cholesterol.
ii. Reducing cAMP concentrations and lipolysis in adipocytes results in a lowering of FFA concentrations and decreasing heptic reesterfication of TG and synthesis of VLDL
iii. Does not represent a vitamin role because it is specific to nicotinic acid and the coenzyme of nicotinic acid is actually mediated through micotinamide
- What is the major deficiency disease associated with niacin; why were major deficiencies seen in central Europe and SE United States, but not in the SW United States, or central Mexico?
a. Niacin deficiency results in the specific deficiency disease called pellagra. They all had diets based heavily on corn which is a poor source of niacin. However, Southwest US and Mexico processed corn in limewater which makes niacin more available.
- What are some of the side effects (toxicities of niacin), which form of niacin are these associated with?
a. Niacin toxicity has been described only with the supplemental form nicotinic acid.
b. Some side effects are flushing effect, increased itching, elevated serum liver enzymes and liver damage.
- What is the vitamin form and two active forms of pantothenic acid; what is the active part of the vitamin; how does this relate to its function?
a. The 2 active co enzymes present in humans are 4 phosphopantethenate and coenzyme A.
b. There are 2 isomers however only D isomer posses biological activity while the L form may interfere with the D isomer’s activity
