Browsing Pathways

Cells typically contain large amounts of C18 and C20 fatty acids. Longer chain fatty acids are found in certain specialized tissues (myelin contains high amounts of C22 and C24 components). Even longer chain fatty acids are derived from either dietary sources or from elongation of C16-CoA or C18-CoA formed by the cytoplasmic fatty acid synthetase system. All of the fatty acids needed by the body can be synthesized from palmitate (C16:0) except the essential, polyunsaturated fatty acids such as linoleate and linolenate. To create longer, shorter, oxidized, reduced fatty acids, palmitic acid is subjected to enzymatic reactions by reductases, hydroxylases, elongases and mixed function oxidases. There are 3 major processes that modify palmitic acid: elongation, desaturation and hydroxylation. Elongation of fatty acids may occur at endoplasmic reticulum where fatty acid molecules of length up to C24 may be produced. Mitochondrial elongation may result in fatty acids up to C16 in length. Fatty acid elongation in mitochondria is essentially the reverse of beta-oxidation for fatty acid oxidation. In particular, both pathways make use of acetyl-CoA acyltransferase, 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase. The final step of fatty acid elongation uses enoyl-CoA reductase (not part of the beta-oxidation pathway). The elongation takes place in the mitochondrial matrix. In liver and kidney fatty acid elongation operates best in the presence of both NADH and NADPH, whereas in heart and skeletal muscle, only NADH is required. The mitochondrial pathway is important for elongating fatty acids containing 14 or fewer carbon atoms. Short chain fatty acids (SCFA) are fatty acids with aliphatic tails of less than six carbons. Medium chain fatty acids (MCFA) are fatty acids with aliphatic tails of 6Š—–12 carbons. Long chain fatty acids (LCFA) are fatty acids with aliphatic tails longer than 12 carbons. Very Long chain fatty acids (VLCFA) are fatty acids with aliphatic tails longer than 22 carbons.

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.

The degradation of fatty acids occurs is many ways, but for the most part in most species it occurs mainly through the beta-oxidation cycle. Take mammals for example, in this subset of species we find that beta-oxidation takes place not only in mitochondria, but in peroxisomes as well. In contrast, it tends to be the case that in plants and fungi beta-oxidation is only seen in peroxisomes. The reason the beta-oxidation cycle is found to occur in both mitochondria and peroxisomes in mammals is thought to be that extremely long chain fatty acids will in fact undergo oxidation in both locations, an initial or first oxidation in peroxisomes and second oxidation in the mitochondria. There is however a difference between the oxidation cycle which occurs in both these organelles. Namely, that the oxidation undergone in peroxisomes does not have any coupling to ATP synthesis, unlike the corresponding oxidation which occurs in the mitochondria. We find rather that electrons are passed to molecules of oxygen, which produces hydrogen peroxide. Moreover, there is an enzyme which is found only peroxisomes which ties into this process. It can turn hydrogen peroxide back into water and oxygen and is catalase. To expound further the differences between the oxidation cycle found in the peroxisomes and the mitchondria consider the following three key differences. One, in the peroxisome the beta-oxidation cycle takes as a necessary input a special enzyme called, peroxisomal carnitine acyltransferase, which is needed to move an activated acyl group from outside the peroxisome to inside it. In mitochondrial oxidation similar but different enzymes are used called carnitine acyltransferase I and II. Difference number two is that oxidation in the peroxisome commences with catalysis induced by an enzyme called acyl CoA oxidase. Also, it should be noted that another enzyme called beta-ketothiolase which aids in peroxisomal beta-oxidation has a substrate specificity which differs from that of the mitochondrial beta-ketothiolase. Turning now to how the oxidation cycle function in mitochondria, note that the mitochondrial beta-oxidation pathway is composed of four repeating reactions that take place with each fatty acid molecule. The oxidation of fatty acid chains is a process of progress through repetition. With each turn of the cycle two carbons are removed from the fatty acid chain and the energy of the chemical bonds once housed by the molecule is captured by the reduced energy carriers NADH and FADH2. Acetyl-CoA is created in this 4 step reaction beta-oxidation process and is sent to the TCA cycle. Once inside the TCA cycle, the process of oxidation continues until even the acetyl-CoA is oxidized to CO2. More NADH and FADH2 result.

Fatty acids constitute a large energy source for the body. The cellular membrane is also made up of fatty acids. During starvation times, fatty acids can provide energy to humans for numerous days. Fatty acid metabolism is also known as beta-oxidation. During metabolism, acetyl CoA is produced that can then enter the citric acid cycle. When ATP is needed, ATP may be generated by increasing fatty acid metabolism. Fatty acid metabolism is essentially the reverse reaction of fatty acid synthesis.

Purine is a water soluble, organic compound. Purines, including purines that have been substituted, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable examples are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The main organ where purine nucleotides are created is the liver. This process starts as 5-phospho-α-ribosyl-1-pyrophosphate, or PRPP, and creates inosine 5’-monophosphate, or IMP. Following a series of reactions, PRPP uses compounds such as tetrahydrofolate derivatives, glycine and ATP, and IMP is produced as a result. Glutamine PRPP amidotransferase catalyzes PRPP into 5-phosphoribosylamine, or PRA. 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted tosuccinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP creates a fork in the road for the creation of purine, as it can either become GMP or AMP. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Purine nucleotides being catabolized creates uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. Nucleotide creation stemming from the purine bases and purine nucleosides happens in steps that are called the “salvage pathways”. The free purine bases phosphoribosylated and reconverted to their respective nucleotides.

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.

A group of heterocyclic aromatic organic compound, pyrimidines are similar in structure to benzene and pyridine and count the nucleic acids cytosine, thymine, and uracil as structural derivatives. The following pathway illustrates a many pyrimidine-associated processes such as nucleotide biosynthesis, degradation, and salvage. This pathway depicts a number of pyrimidine-related processes such as nucleotide biosynthesis, degradation, and salvage. For pyrimidine nucleotide biosynthesis, carbamoyl phosphate derived from the action of carbamoyl phosphate synthetase II (CPS-II) on glutamine and bicarbonate is converted into carbamoyl aspartate by aspartate transcarbamoylase, ATCase. Dihydroorotic acid is subsequently generated by the action of carbamoyl aspartate dehydrogenase on carbamoyl aspartate. Dihydroorotate dehydrogenase then converts dihydroorotic acid to orotic acid. From this point, orotate phosphoribosyltransferase incorporates phosphoribosyl pyrophosphate into (PRPP) to produce orotidine monophosphate. Orotidine-5’-phosphate carboxylase subsequently converts orotidine monophosphate into uridine monophosphate (UMP). UMP is further phosphorylated twice to form UTP; the first instance by uridylate kinase and the second instance by ubiquitous nucleoside diphosphate kinase. UTP moves into the CTP synthesis pathway with the action of CTP synthase which aminates the molecule. The uridine nucleotides are also feedstock for the de novo thymine nucleotides synthesis pathway. DeoxyUMP which is derived from UDP or CDP metabolism is transformed by the action of thymidylate synthase into deoxyTMP of which the methyl group is sourced from N5,N10-methylene THF. THF is subsequently regenerated from DHF via dihydrofolate reductase (DHFR) which is essential for the continuation of thymidylate synthase activity. Serine hydroxymethyl transferase then acts on THF to regenerate N5,N10-THF. Pyrimidine synthesis is a comparatively simpler process than purine synthesis due to a couple of factors; pyrimidine ring structure is assembled as a free base rather being derived from PRPP and there is no branch in the pyrimidine synthesis pathway as opposed to the purine synthesis pathway. For thymidine, the action of thymidine kinase on it (or alternatively deoxyuridine) plays an important role in what is referred to as the salvage pathway to dTTP synthesis. However to form dTMP, the action of thymine phosphorylase and thymidine kinase is required. For deoxycytidine, deoxycytidine kinase is required (deoxycytidine also acts on deoxyadenosine and deoxyguanosine). For uracil, UMP can be formed by the action of uridine phosphorylase and uridine kinase on uracil. Pyrimidine catabolism ultimately results in the formation of the waste products of urea, H2O, and CO2. The product of cytosine breakdown, uracil, can be broken down to N-carbamoyl-β-alanine which can be catabolized into β-alanine. The product of thymine breakdown is β-aminoisobutyrate. The transamination of α-ketoglutarate to glutamate requires both of these breakdown products (β-alanine and β-aminoisobutyrate) to act as amine group donors. The products of this transamination can move through a further reaction that produces malonyl-CoA or methylmalonyl-CoA, a precursor for succinyl-CoA which is used in the Krebs cycle.

Amino sugars are sugar molecules containing an amine group. They make up many polysaccharides including, glycosaminoglycans or mucopolysaccharides.

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.

This pathway depicts the conversion of galactose into glucose, lactose, and other sugar intermediates that may be used for a range of metabolic process. Dietary sources of galactose are numerous, but some of the primary sources in the human diet can be found in milk and milk derivative products. This is because during digestion milk sugars and lactose are hydrolyzed into their molecular constituents (e.g. base monosaccharides). In milk, such monosaccharides include glucose and galactose. The metabolism of the sugar Galactose is occurs almost entirely in the liver, and its metabolism is the consequence of three steps or reactions. First, the phosphorylation of galactose is induced by a special enzyme with the predictable name, galactokinase, and produces galactose 1-phosphate. Second, this biproduct and a second molecule, UDP-glucose, undergo a reaction which leads to the formation of UDP-galactose and glucose 1-phosphate. Thus, this reaction produces 1 molecule of glucose 1-phosphate per molecule of galactose. This is mediated by the enzyme galactose-1-phosphate uridylyltransferase (GALT). The resulting UDP-galactose undergoes epimerization to form UDP-glucose via the enzyme UDP-galactose-4 epimerase (GALE). The UDP-glucose can be used in glucuronidation reactions and other pentose interconversions. In a reaction shared with other pathways, glucose 1-phosphate can be converted into glucose 6-phosphate. There are other pathways associated with galactose metabolism. For instance, galactose can be converted into UDP-glucose by the sequential activities of GALK, UDP-glucose pyrophosphorylase 2 (UGP2), and GALE. Galactose can also be reduced to galactitol by NADPH-dependent aldose reductase. Also shown in this pathway is the conversion of glucose to galactose vis a vis a different process to the ones described earlier. This pathway, called hexoneogenesis, allows mammary glands to produce galactose. It should be noted however, that despite the existence of this pathway of galactose production, the vast majority of galactose in breast milk is actually the result of direct uptake up from the blood, whereas only a small fraction, ~35%, is the result of this de novo process hexoneogenesis. Also depicted in this pathway are the conversions of other dietary di and tri-saccharides (raffinose, manninotriose, melibiose, stachyose) into galactose, glucose and fructose as well as and dietary sugar alcohols (melibitol, galactinol, galactosylglycerol) into sorbitol, myo-inositol, and glycerol.