Browsing Pathways

Ammonia can be rerouted from the urine and recycled into the body for use in nitrogen metabolism. Glutamate and glutamine play an important role in this process. There are many other processes that act to recycle ammonia. asparaginase recycles ammonia from asparagine. Glycine cleavage system generates ammonia from glycine. Histidine ammonia lyase forms ammonia from histidine. Serine dehydratase also produces ammonia by cleaving serine.

Beta-alanine, 3-aminopropanoic acid, is a non-essential amino acid. Beta-Alanine is formed by the proteolytic degradation of beta-alanine containing dipeptides: carnosine, anserine, balenine, and pantothenic acid (vitamin B5). These dipeptides are consumed from protein-rich foods such as chicken, beef, pork, and fish. Beta-Alanine can also be formed in the liver from the breakdown of pyrimidine nucleotides into uracil and dihydrouracil and then metabolized into beta-alanine and beta-aminoisobutyrate. Beta-Alanine can also be formed via the action of aldehyde dehydrogenase on beta-aminoproionaldehyde which is generated from various aliphatic polyamines. Under normal conditions, beta-alanine is metabolized to aspartic acid through the action of glutamate decarboxylase. It addition, it can be converted to malonate semialdehyde and thereby participate in propanoate metabolism. Beta-Alanine is not a proteogenic amino acid. This amino acid is a common athletic supplementation due to its belief to improve performance by increased muscle carnosine levels.

In man, phenylalanine is an essential amino acid which must be supplied in the dietary proteins. Once in the body, phenylalanine may follow any of three paths. It may be (1) incorporated into cellular proteins, (2) converted to phenylpyruvic acid, or (3) converted to tyrosine. Tyrosine is found in many high protein food products such as soy products, chicken, turkey, fish, peanuts, almonds, avocados, bananas, milk, cheese, yogurt, cottage cheese, lima beans, pumpkin seeds, and sesame seeds. Tyrosine can be converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Depicted in this pathway is the conversion of phenylalanine to phenylpyruvate (via amino acid oxidase or tyrosine amino transferase acting on phenylalanine), the incorporation of phenylalanine and/or tyrosine into polypeptides (via tyrosyl tRNA synthetase and phenylalyl tRNA synthetase) and the conversion of phenylalanine to tyrosine via phenylalanine hydroxylase. This reaction functions both as the first step in tyrosine/phenylalanine catabolism by which the body disposes of excess phenylalanine, and as a source of the amino acid tyrosine. The decomposition of L-tyrosine begins with an α-ketoglutarate dependent transamination through the tyrosine transaminase to para-hydroxyphenylpyruvate. The next oxidation step catalyzed by p-hydroxylphenylpyruvate-dioxygenase creates homogentisate. In order to split the aromatic ring of homogentisate, a further dioxygenase, homogentistate-oxygenase, is required to create maleylacetoacetate. Fumarylacetate is created by the action maleylacetoacetate-cis-trans-isomerase through rotation of the carboxyl group created from the hydroxyl group via oxidation. This cis-trans-isomerase contains glutathione as a coenzyme. Fumarylacetoacetate is finally split via fumarylacetoacetate-hydrolase into fumarate (also a metabolite of the citric acid cycle) and acetoacetate (3-ketobutyroate).

Thyroid hormone synthesis is a process that occurs in the thyroid gland in humans that results in the production of thyroid hormones which regulate many different processes in the body, such as metabolism, temperature regulation and growth/development. Thyroid hormone synthesis begins in the nucleus of a thyroid follicular cell, as thyroglobulin synthesis occurs here and is transported to the endoplasmic reticulum. From there, thyroglobulin transported through endocytosis into the intracellular space, and then transported through exocytosis to the follicle colloid. There, thyroglobulin is joined by iodide that has been transported from the blood, through the thyroid follicular cell and arrived in the the follicle colloid using pendrin, and hydrogen peroxide to be catalyzed by thyroid peroxidase, creating thyroglobulin + iodotyrosine. Then, iodide, hydrogen peroxide and thyroidperoxidase create thyroglobulin + 3,5-diiodo-L-tyrosine. Thyroglobulin+3,5-diiodo-L-tyrosine then joins with hydrogen peroxide and thyroid peroxidase to create thyroglobulin + 2-aminoacrylic acid and thyroglobulin+liothyronine. Thyroglobulin + liothyronine then goes through two processes, the first being its transportation into the cell and undergoing of proteolysis, which is followed by liothyronine being transported into the bloodstream. The second process is thyroglobulin + liothyronine being catalyzed by thyroid peroxidase and resulting in the production of thyroglobulin + thyroxine. Thyroglobulin + thyroxine is then transported back into the cell, undergoes proteolysis, and thyroxine alone is transported back out of the cell and into the bloodstream.

The carbocyclic polyol inositol (otherwise known as myo-inositol) has a significant role in physiological systems as many secondary eukaryotic messengers derive their structure from inositol. Examples of secondary messengers derived from inositol include inositol phosphates, phosphatidylinositol (PI), and phosphatidylinositol phosphate (PIP) lipids. Inositol is abundant in many commonly consumed foods such as bran-rich cereals, beans, nuts, and fruit (particularly cantaloupe, melons, and oranges). It can also be synthesized by the body through the conversion of glucose-6-phosphate into mho-inositol under the following pathway: (1) glucose-6-phosphate undergoes isomerization due to the action of inositol-3-phosphate synthase (ASYNA1) which produces myo-inositol 3-phosphate; (2) myo-inositol 3-phosphate undergoes dephosphorylation via the action of inositol monophosphatase (IMPase 1) to produce myo-inositol. From this point, myo-inositol can move through multiple different fates depending on the secondary messenger being synthesized. For phosphatidyliositol, phosphatidylinositol synthase generates it with the substrates CDP-diacylglycerol and myo-inositol. Phosphatidyliositol can be modified further to generate phosphatidylinositol phosphate lipids via the action of class I, II and III phosphoinositide 3-kinases (PI 3-kinases). Other messengers (i.e. inositol phosphates) can be produced with the phospholipase C-mediated hydrolysis of phosphatidylinositol phosphates or with the action of other enzymes that remove or add phosphate groups.

Pyruvate is an intermediate compound in the metabolism of fats, proteins, and carbohydrates. It can be formed from glucose via glycolysis or the transamination of alanine. It can be converted into Acetyl-CoA to be used as the primary energy source for the TCA cycle, or converted into oxaloacetate to replenish TCA cycle intermediates. Pyruvate can also be used to synthesize carbohydrates, fatty acids, ketone bodies, alanine, and steroids. In conditions of inssuficient oxygen or in cells with few mitochondria, pyruvate is reduced to lactate in order to re-oxidize NADH back into NAD+ Pyruvate participates in several key reactions and pathways. In glycolysis, phosphoenolpyruvate (PEP) is converted to pyruvate by pyruvate kinase in an highly exergonic and irreversible reaction. In gluconeogenesis, pyruvate carboxylase and PEP carboxykinase are needed to catalyze the conversion of pyruvate to PEP. In fatty acid synthesis, the pyruvate dehydrogenase complex decarboxylates pyruvate to produce acetyl-CoA. In gluconeogenesis, the carboxylation by pyruvate carboxylase produces oxaloacetate. The fate of pyruvate depends on the cell energy charge. In cells or tissues with a high energy charge pyruvate is directed toward gluconeogenesis, but when the energy charge is low pyruvate is preferentially oxidized to CO2 and H2O in the TCA cycle, with generation of 15 equivalents of ATP per pyruvate. The enzymatic activities of the TCA cycle are located in the mitochondrion. When transported into the mitochondrion, pyruvate encounters two principal metabolizing enzymes: pyruvate carboxylase (a gluconeogenic enzyme) and pyruvate dehydrogenase (PDH). With a high cell-energy charge, acetyl-CoA, is able allosterically to activate pyruvate carboxylase, directing pyruvate toward gluconeogenesis. When the energy charge is low CoA is not acylated, pyruvate carboxylase is inactive, and pyruvate is preferentially metabolized via the PDH complex and the enzymes of the TCA cycle to CO2 and H2O.

Ketone bodies are consisted of acetone, beta-hydroxybutyrate and acetoacetate. In liver cells' mitochondria, acetyl-CoA can synthesize acetoacetate and beta-hydroxybutyrate; and spontaneous decarboxylation of acetoacetate will form acetone. Metabolism of ketone body (also known as ketogenesis) contains several reactions. Acetoacetic acid (acetoacetate) will be catalyzed to form acetoacetyl-CoA irreversibly by 3-oxoacid CoA-transferase 1 that also coupled with interconversion of succinyl-CoA and succinic acid. Acetoacetic acid can also be catalyzed by mitochondrial D-beta-hydroxybutyrate dehydrogenase to form (R)-3-Hydroxybutyric acid with NADH. Ketogenesis occurs mostly during fasting and starvation. Stored fatty acids will be broken down and mobilized to produce large amount of acetyl-CoA for ketogenesis in liver, which can reduce the demand of glucose for other tissues. Acetone cannot be converted back to acetyl-CoA; therefore, they are either breathed out through the lungs or excreted in urine.

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.

The sphingolipid metabolism pathway depicted here describes the synthesis of sphingolipids which include sphingomyelins, ceramides, phosphoceramides, glucosylceramides, galactosylceramides, sulfagalactosylceramides, lactosylceramides, and various other ceramides. The core of a sphingolipid is the long-chain amino alcohol called sphingosine. Amino acylation, with a long-chain fatty acid, at the 2-carbon position of sphingosine yields a ceramide. Sphingolipids are a component of all membranes but are particularly abundant in the myelin sheath. De novo sphingolipid synthesis begins at the cytoplasmic side of the ER (endoplasmic reticulum) with the formation of 3-keto-dihydrosphingosine (also known as 3-ketosphinganine) by the enzyme known as serine palmitoyltransferase (SPT). The preferred substrates for this reaction are palmitoyl-CoA and serine. Next, 3-keto-dihydrosphingosine is reduced to form dihydrosphingosine (also known as sphinganine) via the enzyme 3-ketodihydrosphingosine reductase (KDHR), which is also known as 3-ketosphinganine reductase. Dihydrosphingosine (sphinganine) is acylated by the action of several dihydroceramide synthases (CerS) to form dihydroceramide. Dihydroceramide is then desaturated in the original palmitic portion of the lipid via dihydroceramide desaturase 1 (DES1) to form ceramide. Following the conversion to ceramide, sphingosine is released via the action of ceramidase. Sphingosine can be re-converted into a ceramide by condensation with an acyl-CoA catalyzed by the various CerS enzymes. Ceramide may be phosphorylated by ceramide kinase to form ceramide-1-phosphate. Alternatively, it may be glycosylated by glucosylceramide synthase (to form a glucosylceramide) or galactosylceramide synthase (to form a galactosylceramide). Additionally, it can be converted to sphingomyelin by the addition of a phosphorylcholine headgroup by sphingomyelin synthase (SMS). Sphingomyelins are the only sphingolipids that are phospholipids. Diacylglycerol is also generated via this process. Alternately, ceramide may be broken down by a ceramidase to form sphingosine. Sphingosine may be phosphorylated to form sphingosine-1-phosphate, which may, in turn, be dephosphorylated to regenerate sphingosine. Sphingolipid catabolism allows the reversion of these metabolites to ceramide. The complex glycosphingolipids are hydrolyzed to glucosylceramide and galactosylceramide. These lipids are then hydrolyzed by beta-glucosidases and beta-galactosidases to regenerate ceramide. Similarly, sphingomyelins may be broken down by sphingomyelinase to create ceramides and phosphocholine. The only route by which sphingolipids are converted into non-sphingolipids is through sphingosine-1-phosphate lyase. This forms ethanolamine phosphate and hexadecenal.

Amylase enzymes secreted in saliva by the parotid gland and in the small intestine play an important role in initiating starch digestion. The products of starch digestion are but not limited to maltotriose, maltose, limit dextrin, and glucose. The action of enterocytes of the small intestine microvilli further break down limit dextrins and disaccharides into monosaccharides: glucose, galactose, and fructose. Once released from starch or once ingested, sucrose can be degraded into beta-D-fructose and alpha-D-glucose via lysosomal alpha-glucosidase or sucrose-isomaltase. Beta-D-fructose can be converted to beta-D-fructose-6-phosphate by glucokinase and then to alpha-D-glucose-6-phosphate by the action of glucose phosphate isomerase. Phosphoglucomutase 1 can then act on alpha-D-glucose-6-phosphate (G6P) to generate alpha-D-glucose-1-phosphate. Alpha-D-glucose-1-phosphate (G6P) has several possible fates. It can enter into gluconeogenesis, glycolysis or the nucleotide sugar metabolism pathway. UDP-glucose pyrophosphorylase 2 can convert alpha-D-glucose-1-phosphate into UDP-glucose, which can then be converted to UDP-xylose or UDP-glucuronate and, eventually to glucuronate. UDP-glucose can also serve as a precursor to the synthesis of glycogen via glycogen synthase. Glycogen is an analogue of amylopectin (“plant starch”) and acts as a secondary short-term energy storage for animal cells. It’s formed primarily in liver and muscle tissues, but is also formed at secondary sites such as the central nervous system and the stomach. In both cases it exists as free granules in the cytosol. Glycogen is a crucial element of the glucose cycle as another enzyme, glycogen phosphorylase, cleaves off glycogen from the nonreducing ends of a chain to producer glucose-1-phosphate monomers. From there, the glucose-1-phosphate monomers have three possible fates: (1) enter the glycolysis pathway as glucose-6—phosphate (G6P) to generate energy, (2) enter the pentose phosphate pathway to produce NADPH and pentose sugar, or (3) enter the gluconeogenesis pathway by being dephosphorylated into glucose in liver or kidney tissues. To initiate the process of glycogen chain-lengthening, glycogenin is required because glycogen synthase can only add to existing chains. This action is subsequently followed by the action of glycogen synthase which catalyzes the formation of polymers of UDP-glucose connected by (α1→4) glycosidic bonds to form a glycogen chain. Importantly, amylo (α1→4) to (α1→6) transglycosylase catalyzes glycogen branch formation via the transfer of 6-7 glucose residues from a nonreducing end with greater than 11 residues to the C-6 OH- group in the interior of a glycogen molecule.