Browsing Pathways

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.

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.

Glutathione (GSH) is an low-molecular-weight thiol and antioxidant in various species such as plants, mammals and microbes. Glutathione plays important roles in nutrient metabolism, gene expression, etc. and sufficient protein nutrition is important for maintenance of GSH homeostasis. Glutathione is synthesized from glutamate, cysteine, and glycine sequentially by gamma-glutamylcysteine synthetase and GSH synthetase. L-Glutamic acid and cysteine are synthesized to form gamma-glutamylcysteine by glutamate-cysteine ligase that is powered by ATP. Gamma-glutamylcysteine and glycine can be synthesized to form glutathione by enzyme glutathione synthetase that is powered by ATP, too. Glutathione exists oxidized (GSSG) states and in reduced (GSH) state. Oxidation of glutathione happens due to relatively high concentration of glutathione within cells.

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.

Androstenedione is an endogenous weak androgen steroid hormone that is a precursor of testosterone and other androgens, as well as of estrogens like estrone . Its metabolism occurs primarily in the endoplasmic reticulum (membrane-associated enzymes are coloured dark green in the image). Conversion of androstenedione to testosterone requires the enzyme testosterone 17-beta-dehydrogenase 3. Conversion of androstenedione to estrone involves three successive reactions catalyzed by the enzyme aromatase (cytochrome P450 19A1). Androstenedione can also be converted into etiocholanolone glucuronide, androsterone glucuronide, and adrenosterone. The three-reaction subpathway to synthesize etiocholanolone glucuronide begins with the enzyme 3-oxo-5-beta-steroid 4-dehydrogenase catalyzing the conversion of androstenedione to etiocholanedione. This is followed by the conversion of etiocholanedione to etiocholanolone which is catalyzed by aldo-keto reductase family 1 member C4. Lastly, the large membrane-associated multimer UDP-glucuronosyltransferase 1-1 catalyzes the conversion of etiocholanolone to etiocholanolone glucuronide. The three-reaction subpathway to synthesize androsterone glucuronide begins with the conversion of androstenedione to androstanedione via 3-oxo-5-alpha-steroid 4-dehydrogenase 1. Anstrostanedione is then converted into androsterone via aldo-keto reductase family 1 member C4. The last reaction to form androsterone glucuronide is catalyzed by the large multimer UDP-glucuronosyltransferase 1-1. The two-reaction subpathway to synthesize adrenosterone begins in the mitochondrial inner membrane where androstenedione is first converted into 11beta-hydroxyandrost-4-ene-3,17-dione by the enzyme cytochrome P450 11B1. Following transport to the endoplasmic reticulum, 11beta-hydroxyandrost-4-ene-3,17-dione is converted into adrenosterone via corticosteroid 11-beta-dehydrogenase isozyme 1.

Phosphatidylcholines (PC) are a class of phospholipids that incorporate a phosphocholine headgroup into a diacylglycerol backbone. They are the most abundant phospholipid in eukaryotic cell membranes and has both structural and signalling roles. In eukaryotes, there exist two phosphatidylcholine biosynthesis pathways: the Kennedy pathway and the methylation pathway. The Kennedy pathway begins with the direct phosphorylation of free choline into phosphocholine followed by conversion into CDP-choline and subsequently phosphatidylcholine. It is the major synthesis route in animals. The methylation pathway involves the 3 successive methylations of phosphatidylethanolamine to form phosphatidylcholine. The first reaction of the Kennedy pathway involves the cytosol-localized enzyme choline/ethanolamine kinase catalyzing the conversion of choline into phosphocholine. Second, choline-phosphate cytidylyltransferase, localized to the endoplasmic reticulum membrane, catalyzes the conversion of phosphocholine to CDP-choline. Last, choline/ethanolaminephosphotransferase catalyzes phosphatidylcholine biosynthesis from CDP-choline. It requires either magnesium or manganese ions as cofactors. A parallel Kennedy pathway forms phosphatidylethanolamine from ethanolamine - the only difference being a different enzyme, ethanolamine-phosphate cytidylyltransferase, catalyzing the second step. Phosphatidylethanolamine is also synthesized from phosphatidylserine in the mitochondrial membrane by phosphatidylserine decarboxylase. Phosphatidylethanolamine funnels into the methylation pathway in which phosphatidylethanolamine N-methyltransferase (PEMT) then catalyzes three sequential N-methylation steps to convert phosphatidylethanolamine to phosphatidylcholine. PEMT uses S-adenosyl-L-methionine as a methyl donor.

Carnitine is an ammonium compound that exists in two stereoisomers, of which only L-carnitine is biologically active. Carnitine can be obtained from dietary sources and also biosynthesized. It is necessary for fatty acid oxidation, transporting fatty acids from the cystosol to the mitochondria, where they are broken down via the citric acid cycle to release energy. Carnitine is synthesized from lysine residues in existing proteins. These residues are methylated using lysine methyltransferase enzymes and methyl groups from S-adenosylmethionine, then removed from the protein via hydrolysis. In the next step, the N6,N6,N6-trimethyl-L-lysine is converted to 3-hydroxy-N6,N6,N6-trimethyl-L-lysine t via the mitochondrial enzyme trimethyllysine dioxygenase. The 3-hydroxy-N6,N6,N6-trimethyl-L-lysine is then cleaved to 4-trimethylammoniobutanal and glycine, likely by an aldose identical to serine hydroxymethyltransferase. Next, 4-trimethylammoniobutanal is oxidized by the 4-trimethylaminobutyraldehyde dehydrogenase protein to 4-trimethylammoniobutanoic acid. Finally, 4-trimethylammoniobutanoic acid is transformed into L-carnitine via the enzyme gamma-butyrobetaine dioxygenase. The reactions in the carnitine synthesis pathway occur ubiquitously in the human body with the exception of the last step, as the gamma-butyrobetaine dioxygenase enzyme is found only in the liver and kidney (and at very low levels in the brain). The produced carnitine is then carried to other tissue via a number of transport systems.

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.

Urea, also known as carbamide, is a waste product made by a large variety of living organisms and is the main component of urine. Urea is created in the liver, through a string of reactions that are called the Urea Cycle. This cycle is also called the Ornithine Cycle, as well as the Krebs-Henseleit Cycle. There are some essential compounds required for the completion of this cycle, such as arginine, citrulline and ornithine. Arginine cleaves and creates urea and ornithine, and the reactions that follow see urea residue build up on ornithine, which recreates arginine and keeps the cycle going. Ornithine is transported to the mitochondrial matrix, and once there, ornithine carbamoyltransferase uses carbamoyl phosphate to create citrulline. After this, citrulline is transported to the cytosol. Once here, citrulline and aspartate team up to create argininosuccinic acid. After this, argininosuccinate lyase creates l-arginine. L-arginine finally uses arginase-1 to create ornithine again, which will be transported to the mitochondrial matrix and restart the urea cycle once more.

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.