Answer- Vitamin B6, also called pyridoxine, is one of eight water-soluble B vitamins. There are six forms of vitamin B6: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM)-(figure-1), and their phosphate derivatives: pyridoxal 5′-phosphate (PLP), pyridoxine 5′-phosphate (PNP), and pridoxamine 5′-phospate (PNP). PLP is the active coenzyme form, and has the most importance in human metabolism. In the body, pyridoxine is found primarily in the liver and muscles. Pyridoxine is utilized by the liver to synthesize pyridoxal phosphate (PLP), the active coenzyme form.
Figure 1- Showing forms of B6- a) Pyridoxine , b) Pyridoxal and c) Pyridoxamine.
Vitamin B6 serves as a coenzyme of approximately 100 enzymes that catalyze essential chemical reactions in the human body.
1) It plays an important role in protein, carbohydrate and lipid metabolism. Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially transamination, deamination and decarboxylation reactions. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. Some 80% of the body’s total vitamin B6 is pyridoxal phosphate in muscle, mostly associated with glycogen phosphorylase. This is not available in deficiency, but is released in starvation, when glycogen reserves become depleted, and is then available, especially in liver and kidney, to meet increased requirement for gluconeogenesis from amino acids.
2) It is also required for the synthesis of sphigomyelin and other Sphingolipids
3) Its major function is the production of serotonin from the amino acid tryptophan in the brain and other the synthesis of the neurotransmitters, dopamine, norepinephrine and gamma-aminobutyric acid (GABA) and so it has a role in the regulation of mental processes and mood. These neurotransmitters are produced by decarboxylation where B6 acts as a coenzyme for the respective enzymes.
4) Furthermore, it is involved in the conversion of tryptophan to the vitamin niacin.
5) It is required for the formation of hemoglobin and the growth of red blood cells It acts as coenzyme for the enzyme ALA synthase, in the first step of haem biosynthesis. Deficiency leads to Sideroblastic anemia
6) It promotes absorption of vitamin B12
7) It is required for the production of prostaglandins and hydrochloric acid in the gastrointestinal tract,
8) It is required for the sodium-potassium balance, and in histamine metabolism.
9) As part of the vitamin B-complex it may also be involved in the down regulation of the homocysteine blood level. The enzymes Cystathionine β synthase and Cystathionine lyase require vitamin B6 as coenzyme. Deficiency leads to homocysteinemia
10) Vitamin B6 also plays a role in the improvement of the immune system.
11) In addition, B6 is important in steroid hormone action. Pyridoxal phosphate removes the hormone receptor complex from DNA binding, terminating the action of the hormones. In vitamin B6 deficiency, there is increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D.
12) Vitamin B6 promotes iron excretion and this has been used as a rationale for treatment in iron storage diseases.
13) Vitamin B6 may be helpful in some women with premenstrual dysphoric disorder, also known as premenstrual syndrome (PMS), and may be useful in some cases of gestational diabetes and for protection against metabolic imbalances associated with the use of some oral contraceptives.
Q.2- What are the important functions of niacin in the body?
Answer- The term niacin refers to both nicotinic acid and its amide derivative, nicotinamide (niacinamide)- Figure-2
Figure-2- Showing structure of Nicotinic acid and Nicotinamide
Both are used to form the coenzymes nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+). Niacin is a member of the water-soluble B- vitamin complex. The amino acid tryptophan can be converted to nicotinic acid in humans; therefore niacin is not really a vitamin provided that an adequate dietary supply of tryptophan is available. Some 60 mg of tryptophan is equivalent to 1 mg of dietary niacin.
As many as 200 enzymes require the niacin coenzymes, NAD+ and NADP+, mainly to accept or donate electrons for redox reactions. NAD+ functions most often in energy producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP+ functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of all macromolecules, including fatty acids and cholesterol. Some of the important enzymes requiring NAD+ and NADP+ are as follows-
NAD+ dependent enzymes
1) Glyceraldehyde-3-phosphae dehydrogenase
2) Pyruvate dehydrogenase complex
3) Mitochondrial isocitrate dehydrogenase
4) Alpha keto glutarate dehydrogenase complex
5) Malate dehydrogenase
6) Lactate dehydrogenase
7) Beta hydroxy acyl co A dehydrogenase
8) Cytosolic glycerol-3-phosphate dehydrogenase
NADPH dependent enzymes
1) HMG co A reductase
2) Enoyl reductase
3) Keto acyl reductase
4) Dihydrofolate reductase
5) Met hemoglobin reductase
6) Ribonucleotide reductase
The niacin coenzyme, NAD+, is the substrate (reactant) for two classes of enzymes (mono-ADP-ribosyltransferases and poly-ADP-ribose polymerase) that separate the niacin moiety from NAD+ and transfer ADP-ribose to proteins.
1) Mono-ADP-ribosyltransferases enzymes were first discovered in certain bacteria, where they were found to produce toxins, such as cholera and diphtheria. These enzymes and their products, ADP-ribosylated proteins, have also been found in the cells of mammals and are thought to play a role in cell signaling by affecting G-protein activity. G-proteins are proteins that bind guanosine-5′-triphosphate (GTP) and act as intermediaries in a number of cell-signaling pathways.
2) Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze the transfer of many ADP-ribose units from NAD+ to acceptor proteins. PARPs appear to function in DNA repair and stress responses, cell signaling, transcription, regulation or apoptosis, chromatin structure, and cell differentiation, suggesting a possible role for NAD+ in cancer prevention. At least five different PARPs have been identified, and although their functions are not yet well understood, their existence indicates a potential for considerable consumption of NAD+.
3) A third class of enzymes (ADP-ribosyl cyclase) catalyzes the formation of cyclic ADP-ribose, a molecule that works within cells to provoke the release of calcium ions from internal storage sites and probably also plays a role in cell signaling.
Other functions of niacin in the body
- High doses of nicotinic acid (1.5-4 g/day) can reduce total and low-density lipoprotein cholesterol and triacylglycerols and increase high-density lipoprotein cholesterol in patients at risk of cardiovascular disease.
- Type 1 diabetes mellitus results from the autoimmune destruction of insulin-secreting b-cells in the pancreas. There is evidence that nicotinamide may delay or prevent the development of diabetes.
Flow chart- showing the synthesis and role of NAD in the redox and non redox reactions
Q.3- Discuss the role of niacin as a lipid lowering drug. What is the cause of hot flushes observed in patients on niacin therapy and how can these be treated?
Answer- Nicotinic acid, or niacin, has been used as a lipid-modifying agent for decades. It was previously shown to reduce the flux of nonesterified fatty acids (NEFAs) to the liver, resulting in reduced hepatic TG synthesis and VLDL secretion. Recently a receptor for nicotinic acid called GPR109A has been discovered; it is expressed in adipocytes and, when activated, suppresses the release of NEFA by adipose. Niacin reduces plasma triglyceride and LDL-C levels and raises the plasma concentration of HDL-C. Niacin is also the only currently available lipid-lowering drug that significantly reduces plasma levels of Lp (a). If properly prescribed and monitored, niacin is a safe and effective lipid-lowering agent.
The most frequent side effect of niacin is cutaneous flushing, which is mediated by activation of the same receptor GPR109A in the skin, leading to local generation of prostaglandin D2 production. Flushing can be reduced by formulations that slow the absorption and by taking aspirin prior to dosing.
Q.4- What is the significance of Pantothenic acid in the body?
Answer- Pantothenic acid, also known as vitamin B5, is essential to all forms of life.
Figure 3- Showing structure of Pantothenic acid
Functions of Pantothenic acid
Pantothenic acid is a component of coenzyme A (CoASH) (Figure-4) , an essential coenzyme in a variety of reactions.
Figure-4 -showing the structure of Co enzyme A
CoASH is required for chemical reactions that generate energy from food (fat, carbohydrates, and proteins). The synthesis of essential fats, cholesterol, and steroid hormones requires CoA, as does the synthesis of the neurotransmitter, acetylcholine, and the hormone, melatonin. Heme, a component of hemoglobin, requires a CoA-containing compound for its synthesis. Metabolism of a number of drugs and toxins by the liver requires CoA.
Coenzyme A was named for its role in acetylation reactions. Most acetylated proteins in the body have been modified by the addition of an acetate group that was donated by CoA. Protein acetylation affects the 3-dimensional structure of proteins, potentially altering their function. For example, acetylation reactions can alter the activity of peptide hormones. Protein acetylation appears to play a role in cell division and DNA replication and also affects gene expression by facilitating the transcription of mRNA. Additionally, a number of proteins are modified by the attachment of long-chain fatty acids donated by CoA. These modifications are known as protein acylation and appear to play a central role in cell signaling.
The acyl-carrier protein requires Pantothenic acid in the form of 4′-phosphopantetheine for its activity as an enzyme. The pantetheine moiety is formed after combination of pantothenate with cysteine, which provides the –SH prosthetic group of CoA and ACP. Both CoA and the acyl-carrier protein are required for the synthesis of fatty acids.
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