Browsing Pathways

Nicotinate (niacin) and nicotinamide - more commonly known as vitamin B3 - are precursors of the coenzymes nicotinamide-adenine dinucleotide (NAD+) and nicotinamide-adenine dinucleotide phosphate (NADP+). NAD+ synthesis occurs either de novo from amino acids, or a salvage pathway from nicotinamide. Most organisms use the de novo pathway whereas the savage pathway is only typically found in mammals. The specifics of the de novo pathway varies between organisms, but most begin by forming quinolinic acid (QA) from tryptophan (Trp) in animals, or aspartic acid in some bacteria (intestinal microflora) and plants. Nicotinate-nucleotide pyrophosphorylase converts QA into nicotinic acid mononucleotide (NaMN) by transfering a phosphoribose group. Nicotinamide mononucleotide adenylyltransferase then transfers an adenylate group to form nicotinic acid adenine dinucleotide (NaAD). Lastly, the nicotinic acid group is amidated to form a nicotinamide group, resulting in a molecule of nicotinamide adenine dinucleotide (NAD). Additionally, NAD can be phosphorylated to form NADP. The salvage pathway involves recycling nicotinamide and nicotinamide-containing molecules such as nicotinamide riboside. The precursors are fed into the NAD+ biosynthetic pathwaythrough adenylation and phosphoribosylation reactions. These compounds can be found in the diet, where the mixture of nicotinic acid and nicotinamide are called vitamin B3 or niacin. These compounds are also produced within the body when the nicotinamide group is released from NAD+ in ADP-ribose transfer reactions.

Folate, or folic acid, is a very important B-vitamin involved in cell creation and preservation, as well as the protection of DNA from mutations that can cause cancer. It is commonly found in leafy green vegetables, but is also present in many other foods such as fruit, dairy products, eggs and meat. Folate is imperative during pregnancy as a deficiency will cause neural tube defects in the offspring. Many countries around the world now fortify foods with folic acid to prevent such defects. This pathway begins in the extracellular space, where folic acid is transported into the cell through a proton-coupled folate transporter. From there, dihydrofolate reductase converts folic acid into dihydrofolic acid. Dihydrofolic acid is then created into tetrahydrofolic acid through dihydrofolate reductase. Tetrahydrofolic acid then sparks the beginning of many reactions and subpathways including purine metabolism and histidine metabolism. There are two reactions that tetrahydrofolic acid undergoes, the first being the catalyzation into tetrahydrofolyl-[glu](2) through the enzyme folylpolyglutamate synthase in the mitochondria. Then, tetrahydrofolyl-[glu](2) becomes tetrahydrofolyl-[glu](n) through folylpolyglutamate synthase. The cycle ends with tetrahydrofolyl-[glu](n) reverting to tetrahydrofolyl-[glu](2) in the lysosome through the enzyme gamma-glutamyl hydrolase. The second reaction that begins with tetrahydrofolic acid sees tetrahydrofolic acid turned into 10-formyltetrahydrofolate through c-1-tetrahydrofolate synthase. This loop is completed by cytosolic 10-formyltetrahydrofolate dehydrogenase reverting 10-formyltetrahydrofolate back to tetrahydrofolic acid. Folate is not stored in the body for very long, as it is a water soluble vitamin and is excreted through urine, so it is important to ingest it continually, as your body’s level of folate will decline after a few weeks if the vitamin is avoided.

This pathway depicts the metabolism of propionic acid. Propionic acid in mammals typically arises from the production of the acid by gut or skin microflora. Propionic acid producing bacteria (Propionibacterium sp.) are particularly common in sweat glands of mammals. After entering a cell, the propionic acid (propanoate) then enters the mitochondria where it is converted into propanol adenylate (or propionyl adenylate or propionyl-AMP) via propionyl-CoA synthetase and acetyl-CoA synthetase. The propionyl adenylate then is converted into propionyl coenzyme A (propionyl-CoA) via the same pair of enzymes. Propionyl-CoA is a relatively common compound that can also arise from the metabolic breakdown of fatty acids containing odd numbers of carbon atoms. Propionyl-CoA is also known to arise from the breakdown of some amino acids. Since propanoate has three carbons, propionyl-CoA cannot directly enter the beta-oxidation cycle (which requires two carbons from acetyl-CoA). Therefore, in most vertebrates, propionyl-CoA is carboxylated into D-methylmalonyl-CoA via propionyl-CoA carboxylase. The resulting compound is isomerized into L-methylmalonyl-CoA via methylmalonyl-CoA epimerase. A vitamin B12-dependent enzyme, called methylmalonyl CoA mutase catalyzes the rearrangement of L-methylmalonyl-CoA to succinyl-CoA, which is an intermediate of the citric acid cycle. Also depicted in this pathway is another propionic acid homolog called hydroxypropanoic acid (hydroxypropionate). This compound is also produced by bacteria and imported into cells. Hydroxypropionate can be converted into 3-hydroxypropionyl-CoA. This compound can be either enzymatically converted to acryloyl-CoA and then to propionyl-CoA or it can spontaneously convert to malonyl-CoA. Malonyl-CoA can convert into acetyl-CoA (via acetyl-CoA carboxylase in the cytoplasm or malonyl carboxylase in the mitochondria) whereupon it may enter a variety of pathways. In a rare genetic metabolic disorder called propionic acidemia, propionate acts as a metabolic toxin in liver cells by accumulating in the liver mitochondria as propionyl-CoA and its derivative methylcitrate. Both propionyl-CoA and methylcitrate are known TCA inhibitors. Glial cells are particularly susceptible to propionyl-CoA accumulation. In fact, when propionate is infused into rat brains and take up by the glial cells, it leads to behavioural changes that resemble autism (PMID: 16950524).

Histidine, an amino acid, plays an important role in the creation of proteins. It is unique as an amino acid as it is needed for nucleotide formation. The biosynthesis of histidine in adults begins with the condensation of ATP and PRPP (phosphoribosyl pyrophosphate) to form n-5-phosphoribosyl 1-pyrophosphate (phosphoribosyl-ATP). It is also worth noting that PRPP is the beginning compound for purine and pyrimidine creation. Subsequent histidine biosynthetic steps (from phosphoribosyl-ATP onwards) are likely to occur in the intestinal microflora. Elimination of the phosphate and the opening of the ring in phosphoribosyl-ATP forms phosphoribosyl-forminino-5-aminoimidazole-4-carboxamide ribonucleotide(phosphoribosyl-forminino-AICAR-phosphate). This is subsequently converted to 5-phosphoribulosyl-forminino-5-aminoimidazole-4-carboxamide ribonucleotide. Cleavage of this compound creates imidazole glycerol phosphate and AICAR (aminoimidazolecarboxamide ribonucleotide) with glutamine being involved as an amino group donor. AICAR is used again through the purine pathway while the imidazole glycerol phosphate is converted to imidazole acetal phosphate. Transamination yields histidinol phosphate which is then turned into histidinol, and then, finally, to histidine. L-histidine is catalyzed by histidine ammonia-lyase into urocanic acid. This acid is then converted to 4-imidazolone-5-propionic acid by urocanate hydratase. 4-imidazolone-5-propionic acid is then converted to formiminoglutamic acid, using the enzyme probable imidazolonepropionase. One last reaction occurs to allow for glutamate metabolism, as formiminoglutamic acid is converted to l-glutamic acid through the use of formimidoyltransferase-cyclodeaminase. Histidine is also a precursor for carnosine biosynthesis(via carnosine synthase), with beta-alanine being the rate limiting precursor. Anserine can be synthesized either from carnosine via carnosine N-methyltransferase or from 1-methylhistidine via carnosine synthase. Inversely, cytosolic non-specific dipeptidase catalyzes the synthesis of 1-methylhistidine from anserine. Histidine is found in meat, seeds, nuts and whole grains. It is a very important amino acid in keeping a pH of 7 in the body, as it acts as a shuttle for protons to maintain a balance of acids and bases in the blood and different tissues.

Nucleotide sugars are defined as any nucleotide in which the distal phosphoric residue of a nucleoside 5'-diphosphate is in glycosidic linkage with a monosaccharide or monosaccharide derivative. There are nine sugar nucleotides and they can be classified depending on the type of the nucleoside forming them: UDP-Glc, UDP-Gal, UDP-GlcNAc, UDP-GlcUA, UDP- Xyl, GDP-Man, GDP-Fuc and CMP-NeuNAc. Turning back now to the pathway in question, namely the nucleotide sugar metabolism pathway, it should be noted that the nucleotide sugars play an important role. Indeed, they are donors of certain important residues of sugar which are vital to glycosylation and by extension tot the production of polysaccharides. This process produces the substrates for glycosyltransferases. These sugars have several additional roles. For example, nucleotide sugars serve a vital purpose as the intermediates in interconversions of nucleotide sugars that result in the creation and activation of certain sugars necessary in the glycosylation reaction in certain organisms. Moreover, the process of glycosylation is attributed mostly (though not entirely) to the endoplasmic reticulum/golgi apparatus. Logically then, due to the important role of nucleotide sugars in glycosylation, a plethora of transporters exist which displace the sugars from their point of production, the cytoplasm, to where they are needed. In the case, the endoplasmic reticulum and golgi apparatus.

The glycerolipid metabolism pathway describes the synthesis of glycerolipids such as monoacylglycerols (MAGs), diacylglycerols (DAGs), triacylglycerols (TAGs), phosphatidic acids (PAs), and lysophosphatidic acids (LPAs). The process begins with cytoplasmic 3-phosphoglyceric acid (a product of glycolysis). This molecule is dephosphorylated via the enzyme glycerate kinase to produce glyceric acid. Glyceric acid is then transformed to glycerol (via the action of aldehyde dehydrogenase and aldose reductase). The free, cytoplasmic glycerol can then be phosphorylated to glycerol-3-phosphate through the action of glycerol kinase. Glycerol-3-phosphate can then enter the endoplasmic reticulum where glycerol-3-phosphate acyltransferase (GPAT) may combine various acyl-CoA moieties (which donate acyl groups) to form lysophosphatidic (LPA) or phosphatidic acid (PA). The resulting phosphatidic acids can be dephosphorylated via lipid phosphate phosphohydrolase (also known as phosphatidate phosphatase) to produce diacylglycerols (DAGs). The resulting DAGs can be converted into triacylglycerols (TAGs) via the addition of another acyl group (contributed via acyl-CoA) and the action of 1-acyl-sn-glycerol-3-phosphate acyltransferase. Extracellularly, the triacylglycerols (TAGs) can be converted to monoacylglycerols (MAGs) through the action of hepatic triacylglycerol lipase. In addition to this cytoplasmic route of glycerolipid synthesis, another route via mitochondrial synthesis also exists. This route begins with glycerol-3-phosphate, which can be either derived from dihydroxyacetone phosphate (DHAP), a product of glycolysis (usually in the cytoplasm of liver or adipose tissue cells) or from glycerol itself. Glycerol-3-phosphate in the mitochondria is first acylated via acyl-coenzyme A (acyl-CoA) through the action of mitochondrial glycerol-3-phosphate acyltransferase to form lysophosphatidic acid (LPA). Once synthesized, lysophosphatidic acid is then acylated with another molecule of acyl-CoA via the action of 1-acyl-sn-glycerol-3-phosphate acetyltransferase to yield phosphatidic acid. Phosphatidic acid is then dephosphorylated to form diacylglycerol. Specifically, diacylglycerol is formed by the action of phosphatidate phosphatase (also known as lipid phosphate phosphohydrolase) on phosphatidic acid coupled with the release of a phosphate. The phosphatase exists as 3 isozymes. Diacylglycerol is a precursor to triacylglycerol (triglyceride), which is formed in the addition of a third fatty acid to the diacylglycerol by the action of diglyceride acyltransferase. Since diacylglycerol is synthesized via phosphatidic acid, it will usually contain a saturated fatty acid at the C-1 position on the glycerol moiety and an unsaturated fatty acid at the C-2 position. When the body uses stored fat as a source of energy, glycerol and fatty acids are released into the bloodstream. Fatty acids, stored as triglycerides in humans, are an important and a particularly rich source of energy. The energy yield from a gram of fatty acids is approximately 9 kcal/g (39 kJ/g), compared to 4 kcal/g (17 kJ/g) for carbohydrates. Since the hydrocarbon portion of fatty acids is hydrophobic, these molecules can be stored in a relatively anhydrous (water-free) environment. Fatty acids can hold more than six times the amount of energy than sugars on a weight basis. In other words, if you relied on sugars or carbohydrates to store energy, then you would need to carry 67.5 lb (31 kg) of glycogen to have the energy equivalent to 10 lb (5 kg) of fat.

The degradation of L-lysine happens in liver and it is consisted of seven reactions. L-Lysine is imported into liver through low affinity cationic amino acid transporter 2 (cationic amino acid transporter 2/SLC7A2). Afterwards, L-lysine is imported into mitochondria via mitochondrial ornithine transporter 2. L-Lysine can also be obtained from biotin metabolism. L-Lysine and oxoglutaric acid will be combined to form saccharopine by facilitation of mitochondrial alpha-aminoadipic semialdehyde synthase, and then, mitochondrial alpha-aminoadipic semialdehyde synthase will further breaks saccharopine down to allysine and glutamic acid. Allysine will be degraded to form aminoadipic acid through alpha-aminoadipic semialdehyde dehydrogenase. Oxoadipic acid is formed from catalyzation of mitochondrial kynurenine/alpha-aminoadipate aminotransferase on aminoadipic acid. Oxoadipic acid will be further catalyzed to form glutaryl-CoA, and glutaryl-CoA converts to crotonoyl-CoA, and crotonoyl-CoA transformed to 3-hydroxybutyryl-CoA. 3-Hydroxybutyryl-CoA will form Acetyl-CoA as the final product through the intermediate compound: acetoacetyl-CoA. Acetyl-CoA will undergo citric acid cycle metabolism. Carnitine is another key byproduct of lysine metabolism (not shown in this pathway).

Thiamine, (Vitamin B1), is a compound found in many different foods such as beans, seafood, meats and yogurt. It is usually maintained by the consumption of whole grains. It is an essential part of energy metabolism. This means that thiamine helps convert carbohydrates into energy. Eating carbohydrates increases the need for this vitamin, as your body can only store about 30mg at a time due to the vitamins short half-life. Thiamine was first synthesized in 1936, which was very helpful in researching its properties in relation to beriberi, a vitamin b1 deficiency. This deficiency has been observed mainly in countries where rice is the staple food. Thiamine metabolism begins in the extracellular space, being transported by a thiamine transporter into the cell. Once in the intracellular space, thiamine is converted into thiamine pyrophosphate through the enzyme thiamin pyrophosphate kinase 1. Thiamine pyrophosphate is then converted into thiamine triphosphate, again using the enzyme thiamin pyrophosphatekinase 1. After this, thiamine triphosphate uses thiamine-triphosphatase to revert to thiamine pyrophosphate, which undergoes a reaction using cancer-related nuceloside-triphosphatase to become thiamine monophosphate. This phosphorylated form is a metabolically active form of thiamine, as are the two other compounds, derivatives of thiamine, mentioned previously. The enzymes used in this pathway both stem from the upper small intestine. Thiamine is passed mainly through urine. It is a water-soluble vitamin, which means it dissolves in water and is carried to different parts of the body but is not stored in the body.

Inositol phosphates are a group of molecules that are important for a number of cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation. Inositol phsosphates consist of an inositol (a sixfold alcohol of cyclohexane) phosphorylated at one or more positions. There are a number of different inositol phosphates found in mammals, distinguishable by the number and position of the phosphate groups. Inositol phosphate can be formed either as a product of phosphatidylinositol phosphate metabolism or from glucose 6-phosphate via the enzyme inositol-3-phosphate synthase 1. Conversion between the different types of inositol phosphates then occurs via a number of specific inositol phosphate kinases and phosphatases, which add (kinase) or remove (phosphatase) phosphate groups. The differing roles of the numerous inositol phosphates means that their metabolism must be tightly regulated. This is done via the localization and activation/deactivation of the various kinases and phosphatases, which can be found in the cytoplasm, nucleus or endoplasmic reticulum. The unphosphorylated inositol ring can be used to produce phosphoinositides through phosphatidylinositol phosphate metabolism.

Betaine (or trimethylglycine) is similar to choline (trimethylaminoethanol) but differs in choline's terminal carboxylic acid group trimethylglycine is reduced to a hydroxyl group. Betaine is obtained from diet as betaine or compounds containing choline in foods such as whole grains, beets and spinach. Betaine can also be synthesized from choline in the liver and kidney. First, choline is oxidized to betaine aldehyde by mitochondrial choline oxidase (choline dehydrogenase). Then, betaine aldehyde dehydrogenase oxidizes betaine aldehyde to betaine in the mitochondria or cytoplasm. In the liver, betaine functions as a methyl donor similar to choline, folic acid, S-adenosyl methionine and vitamin B12. Methyl donors are important for liver function, cellular replication and detoxification reactions. Betaine is also involved in the production of carnitine to protect from kidney damage and functions as an osmoprotectant in the inner medulla.