Vitamins class 1 updated 2024 (1).pdf

B-vitamins Intro, B1, B2, B3, B5 BMS200  Overall Outcome At the end of the vitamin lectures, you will be able to describe how our bodies absorb vitamins, convert them into a useful form, and use them at a biochemical level to promote optimal health. You will also be a...

B-vitamins Intro, B1, B2, B3, B5 BMS200  Overall Outcome At the end of the vitamin lectures, you will be able to describe how our bodies absorb vitamins, convert them into a useful form, and use them at a biochemical level to promote optimal health. You will also be able to apply their biochemical mechanisms to treatment of select conditions. Specific objectives to support this outcome can be found in the syllabus and at the start of each vitamin section in the ppts Intro Objectives Classify vitamins as water or lipid soluble, and contrast with respect to general properties of absorption, transport, storage, excretion, toxicity, dosing Discuss general mechanisms of vitamin deficiencies  A patient comes in with fatigue and asking for supplements to help. You know that some vitamins are good for helping for fatigue, but which ones, and why?  What do you already know? Sort the following properties under the headings of “Water Soluble” and “Lipid Soluble”: ▪ Absorbed directly into blood ▪ Typically stored in body ▪ Vitamin A ▪ Typically less chance of toxicity (why?) ▪ Biotin ▪ Frequent dosing (why?)  Background: B-vitamin coenzymes Vitamins are metabolized into larger coenzyme forms ▪ Coenzymes help catalyze specific types of reactions ▪ Example: Review: The FAD coenzyme form of B2 is shown below. What specific reaction does B2 (and B3) coenzymes help catalyze? B2: Riboflavin B2 coenzyme example: FAD  Background: B-vitamin coenzymes Specific Reactions Catalyzed by B2 and B3 Coenzymes: 1. Vitamin B2 (Riboflavin) Coenzymes: FAD and FMN Specific Reactions Oxidation of succinate to fumarate in the citric acid cycle (via succinate dehydrogenase), where FAD is reduced to FADH₂. Fatty acid oxidation, where FAD is reduced during the first step of the beta-oxidation of fatty acids. Electron transport chain (ETC), where FADH₂ is oxidized back to FAD, transferring electrons to the ETC and contributing to ATP production.  Background: B-vitamin coenzymes Vitamin B3 (Niacin) Coenzymes: NAD+ and NADP+ Specific Reactions Glycolysis and citric acid cycle: NAD+ is reduced to NADH during the oxidation of metabolites such as glucose and pyruvate. Lipid and amino acid metabolism: NAD+ and NADP+ participate in the oxidation of lipids and amino acids. Electron transport chain: NADH is oxidized to NAD+, providing electrons that flow through the ETC to ultimately produce ATP.  Background: B-vitamin coenzymes Based on size, which is more likely to diffuse across cell membranes: vitamins or coenzymes? Food Coenzymes Tissues Blood Vitamins Vitamins Trapped in Coenzymes cells, used Intestinal Lumen Keep this in mind when remembering which enzymes help promote absorption, and which help promote metabolization to coenzyme form  Vitamins vs Co-enzymes Vitamins: Vitamins are typically smaller, simpler molecules compared to their coenzyme forms. For example, riboflavin (vitamin B2) or niacin (vitamin B3) are relatively small and can sometimes diffuse across cell membranes, especially if they are lipid-soluble or have appropriate transport mechanisms. Lipid-soluble vitamins (such as vitamins A, D, E, and K) can readily diffuse across cell membranes because they can dissolve in the lipid bilayer. Coenzymes: Coenzymes, like FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), NAD+ (nicotinamide adenine dinucleotide), and NADP+ (nicotinamide adenine dinucleotide phosphate), are generally larger and more complex molecules. They often contain multiple components, such as nucleotide groups, making them bulki and less likely to diffuse across the hydrophobic lipid bilayer of cell membranes without assistance. Additionally, coenzymes are often charged or polar due to their phosphate groups or other functional groups, further decreasing their ability to passively diffuse across cell membranes.  Can a Co-enzyme turn back into a Vitamin? No, a coenzyme cannot turn back into a vitamin. The conversion from a vitamin to a coenzyme is a unidirectional process primarily because vitamins and coenzymes serve different roles and functions in the body.  Key Reasons Why Coenzymes Cannot Become Vitamins Biochemical Conversion: When a vitamin is converted into a coenzyme, it undergoes specific biochemical modifications (such as phosphorylation or the addition of other functional groups) that alter its structure to make it suitable for its role in enzymatic reactions. This process is generally not reversible in the body. Functional Specialization: Vitamins are required from dietary sources to maintain variou physiological functions. Once a vitamin has been converted into its active coenzyme form, it is committed to fulfilling that specific biochemical function (e.g., facilitating an enzymatic reaction). The body does not have a pathway to reconvert coenzymes back into their original vitamin form. Metabolic Pathways: The pathways that convert vitamins to coenzymes are tightly regulated and designed to meet the body's metabolic needs. There are no known pathways or mechanisms to reverse these processes and regenerate the original vitami from its coenzyme form. Biological Context: Vitamins are essential nutrients that the body cannot synthesize (or cannot synthesize in sufficient quantities). They must be obtained from the diet. Since coenzymes are already functionally active and not needed in their original vitamin form, the body does not require a process to convert them back.  Background: B-vitamin deficiencies Brainstorm general mechanisms that can contribute to B-vit deficiencies ▪ Considering the path of a B-vitamin from food, into your body, into your cells, and out in the urine Considering the above, by what mechanism could the following contribute to deficiencies: ▪ Alcoholism ▪ IBS ▪ Stress  Background: B-vitamin deficiencies Inadequate Dietary Intake Malabsorption Conditions Gastrointestinal disorders, Gastric surgeries, Chronic diarrhea Increased Nutrient Requirements - Pregnancy and lactation Rapid growth: Infants, children, and adolescents undergoing rapid growth may require more B-vitamins. Chronic illnesses Medications and Drugs Genetic Factors Alcohol and Substance Abuse Aging Autoimmune Disorders Impaired Utilization** Loss of Vitamins via Excessive excretion Conditions like **chronic kidney disease or Heat or cooking Thiamin: Vitamin B1  Objectives ▪ Relate B1 absorption, metabolism, excretion and testing to the general properties of B-vitamins ▪ Relate the biochemical function of B1 to carbohydrate metabolism (energy production, PPS products) ▪ Relate antithiamin factors found in common foods to B1 deficiency ▪ Briefly discuss beriberi (wet and dry) and Wernicke- Korsakoff-syndrome in the context of B1 deficiency  What do you already know? Which one or more of the following metabolic pathways use B1? A – Glycolysis B – Pentose Phosphate Shunt C – CAC D – Beta oxidation  Pathways that Use B1 Glycolysis: - No Vitamin B1 is not directly involved in the glycolysis pathway. However, it plays an essential role in the next steps after glycolysis (pyruvate dehydrogenase complex). Pentose Phosphate Shunt (also called the Pentose Phosphate Pathway) - Yes Vitamin B1, in its coenzyme form, is required for the activity of the enzyme transketolase, which is a key enzyme in the non-oxidative phase of the pentose phosphate pathway. Transketolase transfers two-carbon units and requires the vitamin B1 coenzyme to function properly. CAC (Citric Acid Cycle, also known as the Krebs Cycle or TCA Cycle): - Yes Vitamin B1 is essential for the pyruvate dehydrogenase complex and the alpha- ketoglutarate dehydrogenase complex, both of which play crucial roles in linking glycolysis to the citric acid cycle and in catalyzing reactions within the cycle. TPP is a coenzyme required for these dehydrogenase enzymes to function. Beta Oxidation - No Vitamin B1 is not directly involved in the beta-oxidation of fatty acids. Beta-oxidation primarily involves enzymes that do not require thiamine for their function.  Structure and function Coenzyme form = TDP (aka TPP) (thiamin diphosphate/pyrophosphate) 2 phosphoryl groups added to make the coenzyme form  Absorption and Metabolism What type of enzyme takes the TDP from food and turns it into thiamin for absorption? What type of enzyme takes absorbed thiamin and metabolizes it to make the TDP coenzyme?  Enzyme that Converts TDP from Food to Thiamin for Absorption: Enzyme: Phosphatase Function: In the digestive tract, phosphatases (such as alkaline phosphatase) are responsible for removing phosphate groups from TDP (thiamin diphosphate) obtained from food converting it into free thiamin.  Enzyme that Converts Absorbed Thiamin into TDP Coenzyme Enzyme = Thiamin pyrophosphokinase (TPK) Function: Once free thiamin is absorbed into the body, it is phosphorylated by thiamin pyrophosphokinase (TPK) an enzyme that adds two phosphate groupto thiamin, converting it into its active coenzyme form, TDP (thiamin diphosphate) or TPP (thiamin pyrophosphate)* Specific functions B1 and Energy ▪ Citric acid cycle PDH rxn Pyruvate DH (prep step) and α-ketoglutarate DH complexes use B1 ▪ Makes acetyl CoA FYI Review: and succinyl Acetyl or CoA for succinyl is transferred CAC from B1 to lipoic acid to CoA. α-KG DH rxn B2 resets the To Know: PDH and α- lipoic acid, B3 KG DH use B1, lipoic resets the B2 acid, B5, B2, B3. NADH  Vitamin B1 (Thiamine) and the Citric Acid Cycle (CAC) Thiamine Pyrophosphate (TPP) as a Coenzyme and used to help: Pyruvate Dehydrogenase Complex: Location in Pathway: Before the Citric Acid Cycle begins Pyruvate dehydrogenase converts pyruvate (the end product of glycolysis) into acetyl- CoA. Role of Thiamine (TPP):** TPP is required as a coenzyme by the **pyruvate dehydrogenase complex**, which catalyzes the decarboxylation of pyruvate to form acetyl-CoA, with the release of CO₂ and the reduction of NAD+ to NADH. Alpha-Ketoglutarate Dehydrogenase Complex: Location in Pathway: Within the Citric Acid Cycle, α-ketoglutarate dehydrogenase converts α-ketoglutarate to succinyl-CoA. Role of Thiamine (TPP): TPP is also a coenzyme for the α-ketoglutarate dehydrogenase complex. This enzyme catalyzes the decarboxylation of α-ketoglutarate to form succinyl- CoA, with the release of CO₂ and the reduction of NAD+ to NADH.  Specific Functions B1 and energy continued ▪ Succinyl CoA is also a substrate for heme synthesis What is the connection of heme to energy? Oxygen is essential for tissues because it is needed for cellular respiration, a process that produces the energy cells need to function. In cellular respiration, oxygen helps convert glucose and other nutrients into adenosine triphosphate (ATP), which powers Heme various cellular activities. Without sufficient oxygen, tissues can’t get the energy they need, which can Hemoglobin lead to cell damage or death. This is why maintaining proper oxygen levels in the body is crucial for overall health. Carries oxygen to tissues Needed to run __?__  Specific functions B1 and Energy: ▪ Pentose Phosphate Shunt TDP helps transketolase enzymes transfer 2C units in the reactions that connect pentoses back to glycolysis energy GLUCOS Glucose 6-P E PPS NADP H Glycolysis Fructose transketolas es 6-P Pentose s Glyceraldehyde-3- P Pyruvat e  Deficiencies Antithiamine factors found in various foods can help contribute to a thiamin deficiency ▪ Some antithiamin factors can break apart thiamin Sulphur dioxide ▪ Preservative predominantly found in dried fruits/vegetables, as well as alcoholic drinks Thiaminases ▪ Enzymes found in some raw fresh water fish, shellfish, ferns Inactivated by heat  Deficiencies ▪ Other antithiamine factors Polyphenols ▪ Ex: Tannic acid (in tea, betel nuts, etc) and caffeic acid (in coffee, red wine, etc) ▪ Can join 2 thiamines together - Why is this a problem? - It Makes it too big to absorb  Why Joining Two Thiamines Is a Problem 1. Biochemical Specificity: ▪ - Cofactor Role: Thiamine acts as a cofactor for enzymes such as transketolase, pyruvate dehydrogenase, and alpha-ketoglutarate dehydrogenase. These enzymes require thiamine in its active form (thiamine diphosphate or TDP) to facilitate the transfer of 2-carbon units or other biochemical transformations. Joining two thiamine molecules would not produce a functional cofactor for these reactions. 2. Lack of Functional Utility: ▪ - No Enhanced Activity: Combining two thiamine molecules does not result in a form that would be more effective in catalyzing reactions. The enzymatic activity requires thiamine to be present as TDP, and the biochemical activity relies on its specific structure and role in the active site of enzymes. 3. Potential Inhibition: ▪ - Interference with Enzyme Function: If an attempt were made to join two thiamine molecules, the resulting compound could potentially interfere with enzyme function, either by blocking the enzyme's active site or by failing to bind effectively. 4. Metabolic Disruption: ▪ - Deficiency in Function: Thiamine's primary role is to help in energy production and metabolism by aiding in decarboxylation reactions. A non-functional or improperly structured form of thiamine would disrupt these crucial metabolic pathways, leading to symptoms of thiamine deficiency such as fatigue, neurological issues, and metabolic disturbances.  Deficiencies How do you think the following pharmaceuticals could contribute to B1 deficiency? ▪ 5-fluorouracil? Chemotherapeutic agent ▪ Works by inhibiting phosphorylation of thiamin How does this cause a deficiency? ▪ Diuretics?  Deficiencies 5-Fluorouracil: Mechanism: 5-Fluorouracil is a chemotherapeutic agent that primarily works by inhibiting the enzyme thymidylate synthase, which is crucial for DNA synthesis in rapidly dividing cells. This disruption in nucleotide synthesis can indirectly affect various metabolic pathways, including those involving thiamine. Thiamine Phosphorylation Inhibition: Specifically, 5-fluorouracil has been shown to inhibit the phosphorylation of thiamine, which is essential for its conversion into its active form, thiamine diphosphate (TDP). TDP is necessary for the proper function of several key enzymes, including those involved in carbohydrate metabolism. Resulting Deficiency: If thiamine cannot be phosphorylated, it becomes unavailable/trapped in its active form, leading to a functional deficiency. This impairs key enzymatic reactions dependent on TDP, such as those in the Pentose Phosphate Pathway and the Krebs cycle, potentially resulting in symptoms of thiamine deficiency like neurological issues and metabolic disturbances.  Deficiencies Diuretics Mechanism: Diuretics increase urine production, which leads to increased excretion of electrolytes and other nutrients, including thiamine. Thiamine Loss: Prolonged use of diuretics can lead to a loss of thiamine through the urine. This increased loss can deplete the body’s thiamine reserves over time, particularly if dietary intake is not sufficient to compensate for the loss. Resulting Deficiency Chronic thiamine loss due to diuretic use can result in thiamine deficiency if the intake is not adequate. Symptoms of thiamine deficiency, such as fatigue, muscle weakness, and neurological issues, may become evident if the deficiency is severe or prolonged. Excreted thru Urine  Deficiencies B1 deficiency adversely affects highly energy dependent tissues, such as heart and brain ▪ Why is energy production so disrupted by B1 deficiency? B1 deficiency can cause nerve conduction issues ▪ What neurotransmitter would be affected? Review: B1 helps convert pyruvate to acetyl CoA - what NT is made using acetyl CoA? Take home message: Expect to see the CNS and/or cardiovascular system affected by B1 deficiency  Energy Production Disruption: Impact of Deficiency: Without adequate thiamine, pyruvate cannot be efficiently converted to acetyl CoA. This impairs the Krebs cycle and reduces ATP production. Since the heart and brain are highly energy-dependent organs, they are particularly vulnerable to the reduced energy supply. Neurological and Cardiovascular Impact: Nerve Conduction Issues: Thiamine deficiency can cause nerve conduction issues due to its role in maintaining myelin sheath integrity and proper nerve function. This often results in symptoms like peripheral neuropathy and cognitive impairments. Neurotransmitter Affected: Acetyl CoA is a precursor for the synthesis of acetylcholine, a neurotransmitter crucial for many aspects of brain function, including memory and muscle control. A deficiency in acetyl CoA production due to inadequate thiamine can reduce acetylcholine synthesis, affecting cognitive function and muscle coordination. CAC makes: 3 NADH, 1FADH2 and 1 GTP for 12 ATP. Also compromises pentoses from entering glycolysis. Deficiency is likely to affect the central nervous system (CNS) and cardiovascular system. Symptoms may include cognitive disturbances, memory issues, muscle weakness, and cardiovascular problems. Deficiencies B1 deficiency can lead to: ▪ Wernicke-Korsakoff Syndrome May be seen with alcoholism Symptoms include confusion and severe memory impairment (CNS) ▪ Beriberi Main symptoms include: ▪ Sensory and motor nerve conduction issues and muscle weakness when the CNS is more affected (“dry” beriberi) ▪ Heart failure, tachycardia etc when the cardiovascular system is more affected (“wet” beriberi)  Testing Testing ▪ Blood test for transketolase (TK) activity Why might this be more accurate than testing B1 levels directly? Draw blood, separate into two tubes. Add TDP to one tube only, measure activity of TK in both tubes ▪ B1 deficiency: Tube with additional TDP shows a 25% increase in activity What is the rationale here? Why would you not see an increase in activity with the addition of TDP if the patient had adequate B1 levels?  Testing Rationale for Testing TK Activity: Thiamine Dependence of TK Transketolase is an enzyme that requires TDP (the active form of thiamine) as a cofactor. Its activity is directly influenced by the availability of TDP. If thiamine levels are low, the enzyme's activity will be reduced because there is insufficient TDP to enable proper enzyme function. Measurement and Interpretation Increased Activity: If the tube with added TDP shows a significant increase (e.g., 25%) in TK activity compared to the control tube, it indicates that the enzyme's activity was previously limited by a lack of TDP. This suggests a functional deficiency of thiamine. No Increase: If there is no significant increase in activity with the addition of TDP, it could imply that thiamine levels are adequate, and the enzyme's activity is not limited by TDP availability. *Blood Levels can be affected by Recent Intake**  Riboflavin: Vitamin B2 Food sources: Meats (especially liver and organ meats), milk products, brewer’s yeast, legumes, eggs, almonds, leafy greens Objectives Relate B2 absorption, metabolism, excretion and testing to the general properties of B-vitamins Relate the biochemical function of B2 to energy production, catabolism of purines, GSH reduction, NT metabolism Briefly provide a rationale for the use of B2 in treatment of migraines and cataracts What do you already know? Which one or more of the following are coenzyme forms of B2: ▪ FAD ▪ NADH ▪ CoA ▪ PLP ▪ FMN  Absorption and Metabolism Which enzyme would be required for absorption vs metabolism? Dinucleotide Flavin Adenine Bright yellow urine Flavin adenine dinucleotide (FAD) METABOLISM ABSORPTION Riboflavin Flavokinase FMN phosphatase FMN FAD FAD synthetase pyrophosphatase FAD  FAD and FMN Absorption: Dietary riboflavin is absorbed in the small intestine in its free form after enzymatic dephosphorylation of FAD and FMN. It is then converted to FMN and FAD in enterocytes and other tissues. Metabolism: Riboflavin is converted into FMN and FAD, which serve as essential coenzymes in redox reactions, energy metabolism, and antioxidant defense. Distribution: FMN and FAD are distributed throughout the body, especially in metabolically active tissues, where they function as coenzymes for various flavoproteins. Excretion: Excess riboflavin, FMN, and FAD are excreted in the urine, with small amounts potentially excreted in bile or feces.  ENERGY B2 and energy ▪ Which of the following pathways make FADH2 for energy? ▪ Glycolysis ▪ Beta oxidation ▪ CAC ▪ Cori cycle (anaerobic respiration) ▪ What same type of enzyme produces FADH2 (and/or NADH) for energy in catabolic pathways?  ENERGY Beta oxidation is the process where fatty acids are broken down to produce acetyl-CoA, and FADH2 is generated during this process. CAC generates FADH2 as one of its products during the oxidation of succinate to fumarate. The same type of enzyme that produces FADH2 (and/or NADH) in these catabolic pathways is known as a **dehydrogenase**. Specifically, in beta oxidation, the enzyme acyl-CoA dehydrogenase produces FADH2 CAC, the enzyme succinate dehydrogenase (which is also part of the electron transport chain complex II) produces FADH2. Similarly, other dehydrogenases in these pathways produce NADH. Beta Oxidation CA C Pyruvate dehydrogenase complex Dehydro- genase Dehydro- genase Alpha-KG dehydrogenase Succinate complex dehydrogenase (also Complex II entry point for FADH2 in ETC)  ENERGY B2 and energy ▪ In addition to being part of the CAC, succinyl CoA can also feed into heme synthesis How does this provide energy? ▪ How does FADH2 provide energy? ▪ Does FMN/FMNH2 have a role in energy production? Succinyl-CoA in Heme Synthesis: ENERGY an intermediate in the citric acid cycle and can also be used in the synthesis of heme, which is a component of hemoglobin and other heme-containing proteins. While the direct role of succinyl-CoA in heme synthesis is not to provide energy, the production of heme is critical for oxygen transport in the blood, which supports aerobic respiration and overall energy metabolism. FADH2 and Energy Production: Role of FADH2: a high-energy electron carrier produced in the citric acid cycle (CAC) and during beta oxidation of fatty acids. It donates electrons to the electron transport chain (ETC) in mitochondria. When FADH2 donates electrons to Complex II of the ETC, it helps to drive the production of ATP through oxidative phosphorylation. Each FADH2 molecule contributes to the creation of about 1.5 ATP molecules. FMN/FMNH2 and Energy Production: FMN/FMNH2 in the Electron Transport Chain: FMN (flavin mononucleotide) is a prosthetic group of Complex I (NADH dehydrogenase) in the electron transport chain. When NADH donates electrons to Complex I, FMN is reduced to FMNH2. FMNH2 then passes electrons through the chain, which helps in generating a proton gradient across the inner mitochondrial membrane. This gradient drives ATP synthesis via ATP synthase. Therefore, FMN (and its reduced form FMNH2) plays a crucial role in the process of energy production by facilitating electron transfer in the ETC. Cytosol FADH2 generated from glycolytic NADH via glycerol phosphate shuttle Cyt. C G-3-P DH Complex I Complex III Complex IV CoQ FMN Complex II (succinate Electron DH) transferrin g DH FADH2 To Know: from CAC FADH2 from 1) FADH2 supplies electrons to NADH from the ETC, leading to ultimate CAC and beta beta ox production of ATP ox 2) FMN acts as an electron carrier in the ETC Rest of picture is review, FYI only Matrix OTHER B2 and antioxidation ▪ Along with B3, B2 helps regenerate the antioxidant glutathione H 2O H 2O + GSH + GSH 2 H 2O GS-SG Glutathione reductase FADH FAD NADPH + 2 H+ NAD +  OTHER Tyrosine B2 and Dopamine neurotransmitter metabolism ▪ Monoamine oxidase NE uses FAD to oxidize NT’s that have an Degradation: amine structure such MAO NE as: NE ▪ Dopamine, epinephrine, norepinephrine α or β Why do we need to Degradatio Post- metabolize NT’s? n: COMT synaptic Cellula receptor r respon se Therapeutic uses and deficiency Given the following therapeutic mechanisms, how might B2 help prevent: ▪ Migraines Migraines may be due to decreased mitochondria energy production in the brain ▪ Cataracts Cataracts may be caused by UV damaged Deficiency ▪ No “hallmark” deficiency. Symptoms include: Fatigue (know this one, provide a rationale) FYI: cheilosis (cracked lips), glossitis (swollen tongue), sore throat Testing Testing ▪ Similar blood test to B1, except the enzyme this time is glutathione reductase If you had a B2 deficiency, would glutathione reductase activity go up or down if additional FAD were added to the test tube? H 2O H 2O + GSH + GSH 2 H 2O GS-SG Glutathione reductase FADH FAD NADPH + 2 H+ NAD +  Testing Here's why: Vitamin B2 (Riboflavin) and FAD Riboflavin is a precursor for the coenzyme FAD (flavin adenine dinucleotide). Glutathione reductase, an enzyme that helps maintain the antioxidant glutathione in its reduced form, requires FAD as a cofactor to function properly. Deficiency Effects: In a B2 deficiency, there would be a shortage of FAD, leading to reduced activity of FAD-dependent enzymes, including glutathione reductase. Adding FAD: By adding additional FAD to the test tube, you are essentially supplementing the enzyme with its necessary cofactor. This should help increase the activity of glutathione reductase, as the enzyme would now have sufficient FAD to catalyze its reactions effectively. Niacin: Vitamin B3 Objectives Relate B3 absorption, metabolism, excretion and testing to the general properties of B-vitamins Relate the biochemical function of B3 to energy production Relate the biochemical function of B3 to ethanol metabolism, fatty acid synthesis, antioxidation via GSH and Vit C Provide a therapeutic mechanism to rationalize the use of B3 for: Raynaud’s, Elevated TG’s and cholesterol, diabetes Develop a hypothesis regarding the mechanism by which high-dose B3 can cause damage in patients with peptic ulcer disease Relate corn-based diets and carcinoid syndrome to the development of B3 def and pellagra What do you already know? Which one or more of the following are coenzyme forms of B3: ▪ FAD ▪ NADH ▪ CoA ▪ NADP+ ▪ FMN  What do you already know? The coenzyme forms of Vitamin B3 (niacin) are: NADH (Nicotinamide Adenine Dinucleotide, reduced form) NADP+ (Nicotinamide Adenine Dinucleotide Phosphate) NADH: This is the reduced form of NAD+ and is involved in various metabolic processes, including the electron transport chain for ATP production. NADP+: This is the oxidized form of NADPH, which is used primarily in anabolic reactions, including biosynthesis and the antioxidant defense system.  Naming Niacin refers to nicotinic acid and/or nicotinamide: Nicotinic acid and nicotinamide can both be used to make NADH/NAD(P)H coenzymes ▪ Most supplements contain nicotinamide. Any idea why nicotinamide rather than nicotinic acid? ▪ Unique to B3: RDA for niacin includes 1/60mg tryptophan, as can also make NAD+ from tryptophan  why nicotinamide rather than nicotinic acid? Nicotinamide is often used in supplements instead of nicotinic acid for several reasons: Fewer Side Effects: Nicotinic acid can cause flushing, a common side effect characterized by redness and warmth of the skin, especially when taken in higher doses. Nicotinamide does not typically cause flushing, making it a more comfortable option for supplementation. Different Metabolic Pathways: Nicotinamide and nicotinic acid both contribute to the production of NAD+ (nicotinamide adenine dinucleotide), but they enter the metabolic pathways in slightly different ways. Nicotinamide is directly used in the synthesis of NAD+ and is more efficiently converted in the body, whereas nicotinic acid has to be converted to NAD+ through additional steps. Safety Profile: Nicotinamide is considered to have a better safety profile compared to high doses of nicotinic acid. It does not affect blood lipid levels or cause liver toxicity at typical supplementation levels, which can be a concern with high doses of nicotinic acid.  Absorption and metabolism Corn contains niacin bound to carbohydrates (niacytin) and small peptides (niacinogen) ▪ What do you think this does to the bioavailability of niacin obtained from corn? Once nicotinamide and nicotinic acid enter the tissues, they are metabolized into NADH ▪ Nicotinamide adenine dinucleotide  Absorption and metabolism Corn contains niacin bound to carbohydrates as niacytin and to small peptides as niacinogen. This binding affects the bioavailability of niacin in several ways: Reduced Bioavailability (Too big for absorption) Niacytin and niacinogen are forms of niacin that are not as easily absorbed by the body compared to free niacin. The binding to carbohydrates and peptides makes it less accessible for absorption in the digestive tract. As a result, the bioavailability of niacin from corn is lower than from other sources where niacin is present in its free form. Nutritional Implications: Because of this reduced bioavailability, individuals relying heavily on corn as their primary source of niacin might be at risk of niacin deficiency if they do not consume other sources of niacin or if the diet is not well-balanced. This is particularly a concern in populations with a diet primarily consisting of corn and lacking other niacin-rich foods. FYI Visual Nicotinamide Nicotin- adenine amide dinucleotide NADH Nucleotide Adenine Nucleotide  Energy B3 and energy ▪ Which of the following catabolic pathways produce NADH for energy? ▪ Glycolysis ▪ Beta oxidation ▪ CAC ▪ Anaerobic respiration ▪ What same type of enzyme produces NADH (and/or FADH2) for energy in catabolic pathways?  Energy Glycolysis: This pathway breaks down glucose into pyruvate, producing NADH in the process. Beta Oxidation: This pathway breaks down fatty acids into acetyl-CoA, generating NADH as well. Citric Acid Cycle (CAC): This cycle oxidizes acetyl-CoA to produce NADH, along with FADH2. Anaerobic Respiration: While it involves the reduction of other molecules and does not directly produce NADH, it does rely on the regeneration of NAD+ from NADH to maintain glycolysis under anaerobic conditions. The same type of enzyme that produces NADH (and/or FADH2) in these catabolic pathways is a dehydrogenase  Specific functions B3 and energy: Glycolysis ▪ Look at the diagram: find the enzyme that produces NADH Where does NADH go next to make energy in aeroboic conditions? What about anaerobic?  Specific functions In glycolysis the enzyme that produces NADH is glyceraldehyde-3-phosphate dehydrogenase. This enzyme catalyzes the conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, and during this reaction, NAD+ is reduced to NADH. Where NADH Goes Next in Aerobic Conditions: Transport into Mitochondria: In aerobic conditions, NADH produced in glycolysis is transported into the mitochondria. This usually involves shuttle systems like the **malate-aspartate shuttle** (in heart and liver cells) or the **glycerol-3-phosphate shuttle** (in muscle cells), which help transfer the electrons from NADH into the mitochondrial matrix. Electron Transport Chain (ETC): Once inside the mitochondria, NADH donates its electrons to **Complex I** of the electron transport chain (ETC). Production of ATP: The electrons transferred from NADH to Complex I pass through the ETC, which is located in the inner mitochondrial membrane. This process generates a proton gradient across the membrane. ATP Synthesis: The proton gradient drives ATP synthesis via ATP synthase, a process known as oxidative phosphorylation. This is how the energy from NADH is ultimately used to produce ATP. Specific functions: B3 and energy: Cori cycle (anaerobic energy) ▪ Lactate dehydrogenase Muscle: Produces NAD+ to keep glycolysis running Liver: Uses NADH to make glucose for muscles for glycolysis Glycolysis produces ATP for energy  Anaerobic energy: Cori cycle - FYI review - See previous slide for “what to know” Anaerobic Glycolysis: Muscle GNG: Liver Conversion of NADH back to NAD+ allows Glucose Glucose for: ATP 1) ATP 1) Continued NAD+ NADH NADH NAD+ production of ATP via Oxaloacetat Pyruvate glycolysis e 2) Production NADH NAD+ Pyruvate lactate. Lactate 2) NAD+ NADH goes to liver for GNG, glucose Lactate Lactate goes back to muscle to make more energy from glycolysis Specific functions: B3 and energy: CAC ▪ All CAC dehydrogenases (including PDH) make NADH, except which one? Hint: This one makes FADH2, and is also part of ETC B3 and energy: Heme ▪ Succinyl CoA (made by alpha KG dehydrogenase) can also be used to make heme Dehydrogenase B3 and energy: Beta ox ▪ Dehydrogenase makes Dehydrogenase NADH Note: one DH makes NADH, and one DH makes FADH2  Specific functions: All CAC dehydrogenases produce NADH except for? Succinate Dehydrogenase which produces FADH2. Succinate dehydrogenase is unique because it also functions as Complex II in the electron transport chain (ETC), where it directly contributes to the production of FADH2. Beta Oxidation Dehydrogenases: In beta oxidation: - Acyl-CoA dehydrogenase produces FADH2. - 3-Hydroxyacyl-CoA dehydrogenase produces **NADH**. These dehydrogenases are crucial for the breakdown of fatty acids and the generation of high-energy electron carriers used in the electron transport chain for ATP production.  Specific functions Other ▪ Dehydrogenases use NAD+ to metabolize alcohol Review slide to follow, details FYI only ▪ NADH (predominantly catabolic) can be converted to NADPH (predominantly anabolic) by what type of enzyme? NADPH can help regenerate antioxidants (vitamin C, GSH) NADPH produced by PPS can be used to make fatty acids Acetyl GLUCO CoA SE NADP FATTY PP F.A. synthesis S H ACIDS Pentose -P- Sugars Metabolism of Alcohol: FYI Review NAD NADH NAD NADH+ H+ H+ Ethanol Acetaldehyde Acetate E = alcohol E = aldehyde dehydrogena dehydrogena se se Alcohol consumption Flushing Back to normal Physiological effects & therapeutic uses Nicotinic acid (NAc) and nicotinamide (NAm) each have unique physiological effects separate from their coenzyme forms ▪ Giving high doses of NAc or NAm can ensure there are enough of these forms to be utilized for therapeutic effects Physiological effects Nicotinic acid: ▪ 1) Causes vasodilatory prostaglandin release Responsible for “niacin flush” (transient) ▪ Review from BMS150: What enzyme can block production of vasodilatory PG’s? Therefore, what type of pharmaceutical can help prevent niacin flush? Cyclooxygenase (COX) X Aspirin Arachidonic Vasodilatory Release Niacin promoted by acid PG’s nicotinic acid “flush”  The enzyme that blocks the production of vasodilatory prostaglandins (PGs) is cyclooxygenase (COX). Niacin flush is caused by the release of prostaglandins, which lead to vasodilation and the associated flushing. To prevent niacin flush, a common approach is to use a type of pharmaceutical that inhibits COX. These are known as nonsteroidal anti-inflammatory drugs (NSAIDs). For example, aspirin is an NSAID that can inhibit COX enzymes and reduce the production of prostaglandins. By doing so, aspirin can help prevent or minimize the flushing reaction that occurs with niacin supplementation. Physiological effects Nicotinic acid: ▪ 2) Causes enhanced fibrinolysis Actions on plasmin (increases) and fibrinogen (decreases) ▪ Helps prevent clot buildup, thus improving blood flow Nicotinic acid Nicotinic acid (-) (+) Thrombin Plasmin Fibrinogen Fibrin Clot Clot Dissolution Physiological effects Nicotinic acid: ▪ 3) Improves lipid profile: Decreases circulating VDLD/LDL and increases HDL ▪ LDL: Carries cholesterol to tissues for use (good) Can become oxidized and contribute to plaque formation atherosclerosis (bad) ▪ HDL: Picks up excess cholesterol from tissues (including plaques) and can carry back to liver for excretion (good) Physiological effects Nicotinic acid ▪ 3) Improved lipid profile continued NAc can decrease VLDL/LDL by blocking lipolysis in adipose tissue ▪ Diagram the connection between adipose and liver with respect to ffa, VLDL, LDL. Add in effect of NAc. NAc can increase HDL by downregulation of HDL receptors that internalize and catabolize HDL ▪ Allows HDL to circulate longer and pick up more cholesterol  Connecting the Concepts Adipose Tissue → Releases FFAs → Bloodstream → Transports FFAs bound to albumin → Liver Liver: Takes up FFAs → Re-esterifies them to triglycerides → Packages into VLDL → Releases into Bloodstream VLDL is converted to LDL through lipolysis in the bloodstream. NAC: Decreases oxidative stress → Reduces lipolysis in adipose tissue (less FFA release). Enhances antioxidant capacity → Modulates lipid metabolism in the liver (less VLDL production, reduced LDL levels).  Physiological Effects: Review at home Nicotinic acid: Application ▪ Raynaud’s phenomenon Condition characterized by spasm of digital arteries, especially in response to cold or stress, causing numbness and tingling in fingers/toes Nicotinic acid may provide acute relief by promoting vasodilation ▪ Review: What is the vasodilatory mechanism? ▪ Atherosclerosis Condition characterized by narrowing and hardening of arteries Review: Nicotinic can improve blood flow by enhancing fibrinolysis and decreasing ? Physiological effects Histamine Nicotinic acid: Other H2-receptor ▪ 4) Increased histamine release Connect the dots as to why NAc may cause damage in a patient with peptic Parietal ulcer disease Cell ▪ 5) Potential for hyperglycemia Could be partially due to decreased glucokinase phosphorylation of glucose Secretion of ▪ How could this contribute to ? to make ? increased blood sugar? Increases risk of diabetes in pre- diabetic patients Nicotinic Acid and Peptic Ulcer Disease: Increased Histamine Release Nicotinic acid (niacin) can cause increased histamine release, which is a mediator of inflammation and vasodilation. In the context of peptic ulcer disease, this increased histamine release can exacerbate ulcer symptoms because: Histamine Stimulates Gastric Acid Secretion: Histamine binds to H2 receptors in the stomach lining, promoting gastric acid secretion. In patients with peptic ulcer disease, excessive gastric acid can worsen the condition by irritating the ulcerated mucosa and increasing ulcer pain or bleeding. Compounding Existing Gastric Irritation For those already suffering from ulcers, the additional stimulation of gastric acid secretion by histamine can aggravate symptoms and potentially lead to complications such as ulcer bleeding or perforation. Nicotinic Acid and Hyperglycemia: Potential for Hyperglycemia: Niacin can lead to elevated blood glucose levels. One mechanism for this involves decreased phosphorylation of glucose by glucokinase. Here's how this contributes to increased blood sugar: Role of Glucokinase: Glucokinase is an enzyme that helps regulate blood glucose levels by phosphorylating glucose to glucose-6-phosphate in the liver, which is an important step in glucose metabolism and storage. Decreased Glucokinase Activity: When glucokinase activity is reduced, glucose is less efficiently phosphorylated and trapped in the liver cells. This leads to higher levels of free glucose in the bloodstream because less glucose is being converted to glycogen or other metabolic intermediates. Increased Blood Sugar: With decreased glucokinase activity, there is less glucose uptake and storage in the liver, contributing to elevated blood sugar levels. This effect can increase the risk of hyperglycemia and potentially exacerbate diabetes in pre-diabetic patients. Increased Diabetes Risk: For individuals with pre-diabetes or those at risk for diabetes, the impairment in glucose regulation caused by niacin can worsen glycemic control and increase the risk of developing type 2 diabetes.  Physiological effects Nicotinamide ▪ Does not have the same effects just listed for NAc Not associated with niacin flush Not associated with same therapeutic uses ▪ NAm can protect insulin-secreting pancreatic beta cells from damage Does not necessarily protect against development of diabetes ▪ FYI: NAm may also decrease insulin sensitivity, which could explain why improved beta cell function does not translate well to better glycemic control Deficiency Symptoms ▪ Pellagra: dementia, dermatitis, diarrhea, death Causes ▪ Corn-based diet B3 in niacytin or niacinogen form How can each of these contribute Low in tryptophan to pellagra? Why is pellagra is not common in Mexico and Central America, which have largely corn-based diets? ▪ Carcinoid syndrome Condition of increased secretion of serotonin (and other catecholamines) ▪ Why would this cause pellagra? FYI Toxicity FYI: High dose B3 can be associated with liver toxicity, especially nicotinic acid forms Pantothenic acid: Vitamin B5 Objectives Relate B5 absorption, metabolism, excretion and testing to the general properties of B-vitamins Relate the biochemical function of B5 to energy production, synthesis reactions (fatty acids, lipids, cholesterol, ketones) Relate the biochemical function of B5 to the B5 deficiency symptoms of listlessness/fatigue Relate “burning foot syndrome” to B5 deficiency  What do you already know? The most common coenzyme form of B5 is Coenzyme A (CoA). List 2-3 CoA’s you have heard about in BMS so far, and their general functions.  What do you already know? List 2-3 CoA’s you have heard about in BMS so far, and their general functions. Acetyl CoA – CAC, end of beta ox. Creation of HMG CoA for ketones, cholesterol… HMGCoA – cholesterol, ketones Succinyl CoA – CAC, heme Fatty acyl CoA – used for TG and phospholipids synthesis and start of beta ox Structure and function To know: Has S to carry acyl groups To know: What role would kinases and phosphatas es play in absorption vs metabolism ? Phosphate  B5 —> CoA Citric Acid Cycle (CAC:) Acetyl-CoA is a primary substrate that enters the cycle to produce energy. Additionally, succinyl-CoA, another CoA derivative, is an intermediate in the cycle. Vitamin B5 is critical for synthesizing CoA, which is necessary for these processes. Beta Oxidation: This pathway involves the breakdown of fatty acids to produce acetyl-CoA. Fatty acyl-CoA, derived from fatty acids, is the substrate for beta oxidation, and acetyl-CoA is the end product. CoA is vital for this process as it helps in the activation and breakdown of fatty acids. Ketolysis: In ketolysis, acetyl-CoA is generated from ketone bodies, which are alternative energy sources, especially during periods of fasting or prolonged exercise. CoA is essential for the utilization of these ketone bodies. Heme Synthesis Succinyl-CoA, a product of the CAC, is a substrate for the synthesis of heme, a crucial component of hemoglobin. CoA, synthesized from Vitamin B5, is necessary for the production of succinyl-CoA, which in turn supports heme synthesis. Specific Functions B5 and energy ▪ CAC: Acetyl CoA, succinyl CoA (substrates) ▪ Beta oxidation: Fatty acyl CoA (substrate), acetyl CoA (product) ▪ Ketolysis: Acetyl CoA (product) ▪ Heme synthesis: Succinyl CoA (substrate) Beta ox Fatty Acyl Keto- Acetyl CoA CoA lysis Ketone s Energ CAC y Succinyl Also used for heme CoA synthesis Specific Functions B5 and synthesis ▪ Fatty acids: Next 2 green CoA: makes acetyl CoA and malonyl CoA slides are substrates review, details Also: Part of fatty acid synthetase complex are FYI only ▪ Phospholipids and triglycerides Fatty acyl CoA substrates ▪ Cholesterol and ketones Acetyl CoA Acetyl CoA = substrate to make HMG-CoA HMG CoA Ketones Cholesterol Specific functions – FYI Review Fatty acid synthesis: 2 roles for B5 ▪ Acetyl CoA and malonyl CoA are substrates ▪ ACP (acyl carrier protein) part of fatty acid synthase includes a portion of CoA (FYI phosphopantethine portion, which is CoA minus the AMP) The S group binds the malonyl substrate Fatty acid synthase B5 Cys S S Malonyl and acetyl C=O C=O groups combine to Malonyl start the fatty acid group from CH2 CH3 chain malonyl CoA COO- Acetyl group from acetyl Specific functions – FYI Review Lipid synthesis ▪ Fatty acyl CoAs provide the fatty acid chains for triglyceride and phospholipid synthesis O O O O H2C-OH R-C-SCoA H2C-OC-R R-C- H2C-OC-R SCoA O HO-CH HO-CH R-C-O -CH H2C-OPO3-2 H2C-OPO3-2 H2C- OPO3-2 Use another Add a head acyl CoA to group to make make a a phospholipid triglyceride  Deficiency Deficiency symptoms ▪ Burning Foot Syndrome (rare) Burning sensation in feet exacerbated by heat and diminished by cold ▪ FYI – good for hair? ▪ FYI – “antistress” vitamin? To be explored in NMT ▪ Fatigue and listlessness What is the rationale? Acetyl CoA ▪ Energy pathways – which ones? ▪ Heme synthesis – what is the connection to fatigue and listlessness? HMG CoA ▪ Cortisol to help maintain blood glucose – what is the connection to B5? Cholesterol Steroid hormones