Niacin and Vitamin B12 Metabolic importance

Vitamins are chemically unrelated organic compounds which can be used in many metabolic process. The vitamin B complex are water soluble vitamins that are needed to form the coenzymes or enzymes in metabolic pathways. Niacin is used to produce NAD+ which is used in cellular respiration and NADP+ used in the pentose phosphate pathway and would lead to someone developing pellagra. Additionally, vitamin B12 is used to form cofactors required in the conversion of homocysteine to methionine an amino acid needed in the protein synthesis. Also in the isomerization of methylmalonyl-CoA to Succinyl-CoA, an intermediate in the TCA cycle, and a deficiency can lead to the development of pernicious anemia (Ferrier, 2014).


Niacin or nicotinic acid forms nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NAPH+) which are biologically coenzymes required for metabolic processes such as cellular respiration and the pentose phosphate pathway. They are the two most abundant cofactors in the eukaryotic cell and both perform different metabolic roles in the cell but they cannot be interchanged. (Ferrier, 2014).

Aerobic respiration needs NADH to be oxidized in the electron transport chain, and for each NADH molecule there are three molecules of ATP produced. In glucose there is a net product of 2 NADH which are created by the NAD+ acting as a hydrogen acceptor.
Stage 1 of glycolysis involves three parts: starting with a phosphorylation, then an isomerization reaction and lastly a second phosphorylation reaction. The product of the reactions is fructose 1,6-bisphosphate. These steps in the glycolytic pathway are needed for the glucose to stay in the cell. Additionally, the fructose 1,6- bisphosphate is easy to convert to phosphorylated three-carbon units. The second part of the glycolysis involves the conversion of the fructose 1,6-bisphosphate into two different three carbon units which interconvert easily. In the third part, the three carbon units are converted to pyruvate and there is a net production of two ATP. In the citric acid cycle, the is a net production of 6 NADH molecules which can be used in the electron transport chain. The NADH is produced by four Oxidation-reduction reactions where three pairs of electrons are transferred to NAD+ and one pair to FAD (Ferrier, 2014).

Taken from- Biochemistry 5th edition
Fig 1- glycolysis
The diagram shows the metabolic process of glycolysis where glucose is trapped in the cell then converted to three carbon carbohydrates and lastly ATP is produced. There is a net production of 2 ATP in glycolysis .Two NAD+ act as hydrogen acceptors to produce 2 NADH to be used in the electron transport chain(Berg , 2002).

Taken from- biochemistry 5th edition
Fig 2- citric acid cycle
This diagram shows the citric acid cycle where 6 NADH molecules are produced from NAD+ acting as a hydrogen acceptors. The product of glycolysis, pyruvate, converts to acetyl CoA which then enters the cycle. There were three oxidation reduction reactions in the cycle which are where the NADH is produced(Berg , 2002).

The NADH produced in glycolysis cannot enter the mitochondria so instead the electrons from the molecules enter instead (Berg , 2002).The glycerol 3-phospahte shuttle is one of the ways electrons can enter the electron transport chain. The shuttle starts with a pair of electrons being transferred from NADH to dihydroxyacetone phosphate which forms glycerol 3-phosphate. This reaction uses the enzyme glycerol 3-phosphate dehydrogenase and occurs in the cytoplasm. Then the glycerol 3-phosphate goes through oxidation to dihydroxyacetone phosphate by the glycerol 3-phosphate dehydrogenase (the membrane bound version of the enzyme) on the inner mitochondrial membrane. The glycerol 3-phosphate then moves the electron pair to a FAD prosthetic group in this enzyme which forms FADH2 and this reaction also regenerates the original electron acceptor dihydroxyacetone phosphate(Ferrier, 2014).

Taken from — biochemistry 5th edition

Fig 3- Electrons from NADH produced in glycolysis enter the electron transport chain in the glycerol 3-phosphate shuttle. Where a pair of electrons from the NADH are transferred to dihydroxyacetone phosphate forming glycerol 3-phosphate. Which is then reoxidised on the membrane of the mitochondria by glycerol 3-phosphate dehydrogenase (Ferrier, 2014)

Another way the electrons can be transferred in to the mitochondria is by another shuttle called the malate-aspartate shuttle. This reaction is controlled by four different enzymes and two membrane carriers. In the shuttle, oxaloacetate accepts the electrons from NADH leading to the formation of malate which can traverse the inner mitochondrial membrane. After that the malate is then reoxidized by NAD+ in the matrix of the mitochondria to form NADH and the enzyme used is the citric acid cycle enzyme malate dehydrogenase(Ferrier, 2014).

In the second part of the shuttle the oxaloacetate needs to pass through the mitochondrial membrane but cannot so this means that a transamination reaction has to occur that forms aspartate, which is transported but into the cytoplasm of the cell. The formation of aspartate and α-ketoglutarate occurs by mitochondrial glutamate donating an amino group and enters the cytoplasm and the cycle is begins again. This shuttle is different from the glycerol 3-phosphate as it is reversible and can only happen if the mitochondria if the if the ratio of NADH/NAD+ is at a higher than the level in the mitochondria (Ferrier, 2014).

Taken from -molecular cell biology 4th edition

Fig 4- the malate shuttle
This diagram represents the malate shuttle where the electron of NADH produced in the cytoplasm are transported in to the mitochondria by malate dehydrogenase. The electrons can only be transported in to the mitochondria if the the contration of NADH is higher out of the cell(Ferrier,2014).

In the electron transport chain the hydride ions carried by the NADH are transferred to the protein complex I (dehydrogenase) and tightly to the flavin mononucleotide a coenzyme which is closely related to the coenzyme FAD that accepts the two hydrogen atoms becoming FMNH2. At complex I electrons flows from NADH to FMN to the iron in the iron sulfur complex centers then to coenzyme Q. Coenzyme Q is a mobile electron carrier and can accept hydrogen atoms from NADH dehydrogenase (complex I), complex II and from other mitochondrial dehydrogenases. As the electrons flow they loss energy and this energy is used to push protons across the inner of the mitochondrial membrane. Ferrier, 2014).

Taken from — molecular cell biology 4th edition
Fig 5- the electron transport chain
The diagram it shows the electron transport chain Where the NADH attaches to the protein complex I then is ferried the chain producing ATP where oxygen acts as the final electron acceptor and water is produced.

NADP+ is needed in for the pentose phosphate pathway to produce NADPH which is required for reductive biosynthesis for example the biosynthesis of cholesterol and fatty acid.The pentose phosphate pathway has two parts: the first part is oxidative generation of NADPH and the second part is the non-oxidative interconversion of sugars. The oxidative phase is where NADPH is made which occurs when glucose 6-phosphate is oxidized to ribose 5-phosphate. (Ferrier, 2014). The non-oxidative part of the pathway produces excesses 5 carbon sugars which are intermediates and the 5 carbon sugars for nucleotide biosynthesis (Berg , 2002).

Taken from — biochemistry 5th edition
Fig 6-the pentose phosphate pathway
The diagram shows the 2 stages of the pentose phosphate pathway the oxidative stage and the non-oxidative stage of the pathway where NADPH is produced which is needed for reductive biosynthesis. (Berg, 2002).

Pellagra is a disease which occurs by a deficiency in niacin or tryptophan which can degrade to niacin then NAD through the kynurenine pathway. When there are low levels of niacin it can slow down steps in the kynurenine pathway which would lead to the slowdown the of synthesis of the cofactors NAD+ and NADP+ so undermining the activities of the hundreds of enzymes involved in various vital biochemical processes, including energy production. Changes of these important functions is the main reason the symptoms of dementia, diarrhea, dermatitis and dementia are the main symptoms, as it targets the skin and gastric tracts which have the high cellular turnover and the brain which has high energy requirements. Pellagra can be reversed by dietary supplements and there are laboratory methods for assessing niacin in the body. The normal way to diagnosis pellagra is to assess the levels of urinary products of niacin metabolism, which is done normally by urinary excretion of N1-methylnicotinamide and Ratio of niacin metabolites in urine (Crook ,2014)

Vitamin B12

Vitamin B12 cobalamin is used in the remethylation pathway of homocysteine to methionine and about half of methionine is produced this way. Homocysteine is converted to methionine using the enzyme methionine synthase and the coenzyme methyl cobalamin which needs vitamin B12 to form. This pathway involves, homocysteine acquiring a methyl group when 5-methyltetrahydrofolate converts to tetrahydrofolate. Methionine is a Proteinogenic amino acids that are building blocks to proteins, and are incorporated into proteins during translation(Ferrier, 2014)

Take from biochemistry 6TH edition
Fig 7- remethylation pathway of homocysteine to methionine
This diagram shows the production of methionine. Which requires the a coenzyme of vitamin B methyl cobalamin and methionine forms by homocysteine gaining a methyl group 5-methyltetrahydrofolate.

Vitamin B12 also is needed to form Methylmalonyl Coenzyme A mutase, which is the enzyme involved in the isomerization of methylmalonyl-CoA to Succinyl-CoA. The breakdown of cholesterol, the amino acids (valine, isoleucine, methionine, and threonine) and also odd-chain fatty acids produce the methylmalonyl-CoA. Which is then broken down using Methylmalonyl Coenzymes A mutase to produce Succinyl-CoA which is an intermediate in the Citric acid cycle (Ferrier, 2014).

Take from — Biochemistry 6th edition
Fig 8- the isomerization of methylmalonyl CoA
This diagram shows the isomerization methylmalonyl CoA which is made by degradation of fatty and amino acid chains which an odd number of carbon atoms. The isomerization produces Succinyl CoA which is a n intermediate in the citric acid cycle.

The B12-dependent methionine is needed for normal blood formation and neurological function. Pernicious anemia is the best known deficiency disease of vitamin B12 and can be caused end stage of an autoimmune disorder which leads to the loss of gastric parietal cells or by damage to the gastric cells by stomach surgery. The damage and loss to the cells reduces which then can lead to a stop in production of intrinsic factor, which prevents the uptake of the vitamin. Pernicious anemia can lead to many symptoms for example fatigue and shortness of breath it can also lead to neurological symptoms like memory loss dizziness and numbness in hands and feet. The normal test for vitamin B12 deficiency is by testing the levels of total plasma cobalamin however it has been shown that measuring the holoTC (which is plasma vitamin B12 bound to transcobalamin )is equally accurate so both are used to diagnosis. Additional ways to measure deficiency is by the metabolic process for example cystathionine, methylmalonic acid and 2-methylcitric acid allows the earlier detection of a metabolic disturbances in the body. Plasma homocysteine however is not normally used as an indicator of vitamin B12 levels in the body because conditions such as folate or vitamin B6 deficiencies can also cause higher concentrations plasma homocysteine. Serum cystathionine concentrations are usually elevated in cobalamin deficiency but also in folate and B6 deficiencies so is not the most accurate way to measure deficiency (Singer and Elmadfa ,2009)

In conclusion the vitamin B complex are water soluble vitamin required in many metabolic pathways. Niacin forms NAD+ which is required for cellular respiration and NADP+ which is needed to form NADPH in the pentose phosphate pathway which is then used as a reductive agent in biosynthesis. When someone is a deficiency in the vitamin they will develop Pellagra which can be diagnosed by testing urine for niacin N1-methylnicotinamide and the ratio of niacin metabolites. Vitamin B12 is needed to form coenzyme the reaction that converts homocysteine to methionine and for another reaction that converts l-methylmalonyl-coenzyme A (CoA) to Succinyl-CoA. When someone is deficient they can develop Pernicious anemia which is most commonly diagnosed by testing the blood for plasma cobalamin and the measurements of holoTC (Ferrier, 2014)

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