Browsing Pathways

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism . Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG.

Phosphatidylethanolamines (PE) are the second most abundant phospholipid in eukaryotic cell membranes, and contrary to phosphatidylcholine, it is concentrated with phosphatidylserine in the cell membrane's inner leaflet. In Homo sapiens, there exist two phosphatidylethanolamine biosynthesis pathways. In the visualization, all enzymes that are dark green in colour are membrane-localized. The first pathway synthesizes phosphatidylethanolamine from ethanolamine via the Kennedy pathway. First, the cytosol-localized enzyme choline/ethanolamine kinase catalyzes choline to convert to phosphocholine. Second, choline-phosphate cytidylyltransferase, localized to the endoplasmic reticulum membrane, catalyzes phosphocholine to convert to CDP-choline. Last, choline/ethanolaminephosphotransferase catalyzes phosphatidylcholine biosynthesis from CDP-choline. It requires either magnesium or manganese ions as cofactors. Phosphatidylethanolamine is also synthesized from phosphatidylserine at the mitochondrial inner membrane by phosphatidylserine decarboxylase. Phosphatidylserine, itself, is synthesized using a base-exchange reaction with phosphatidylcholine. This reaction is catalyzed by phosphatidylserine synthase which is located in the endoplasmic reticulum membrane.

This pathway describes the production and subsequent metabolism of arachidonic acid, an omega-6 fatty acid. In resting cells arachidonic acid is present in the phospholipids (especially phosphatidylethanolamine and phosphatidylcholine) of membranes of the body’s cells, and is particularly abundant in the brain. Typically a receptor-dependent event, requiring a transducing G protein, initiates phospholipid hydrolysis and releases the fatty acid into the intracellular medium. Three enzymes mediate this deacylation reaction including phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD). Once released, free arachidonate has three possible fates: 1) reincorporation into phospholipids, 2) diffusion outside the cell, and 3) metabolism. Arachidonate metabolism is carried out by three distinct enzyme classes: cyclooxygenases, lipoxygenases, and cytochrome P450’s. Specifically, the enzymes cyclooxygenase and peroxidase lead to the synthesis of prostaglandin H2, which in turn is used to produce the prostaglandins, prostacyclin, and thromboxanes. The enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins. Some arachidonic acid is converted into midchain HETEs, omega-chain HETEs, dihydroxyeicosatrienoic acids (DHETs), and epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenase hydroxylase activity. Several products of these pathways act within neurons to modulate the activities of ion channels, protein kinases, ion pumps, and neurotransmitter uptake systems, affecting processes such as cellular proliferation, inflammation, and hemostasis. The newly formed eicosanoids may also exit the cell of origin and bind to G-protein-coupled receptors present on nearby neurons or glial cells.

Valine, isoleuciine, and leucine are essential amino acids and are identified as the branched-chain amino acids (BCAAs). The catabolism of all three amino acids starts in muscle and yields NADH and FADH2 which can be utilized for ATP generation. The catabolism of all three of these amino acids uses the same enzymes in the first two steps. The first step in each case is a transamination using a single BCAA aminotransferase, with α-ketoglutarate as the amine acceptor. As a result, three different α-keto acids are produced and are oxidized using a common branched-chain α-keto acid dehydrogenase (BCKD), yielding the three different CoA derivatives. Isovaleryl-CoA is produced from leucine by these two reactions, alpha-methylbutyryl-CoA from isoleucine, and isobutyryl-CoA from valine. These acyl-CoA’s undergo dehydrogenation, catalyzed by three different but related enzymes, and the breakdown pathways then diverge. Leucine is ultimately converted into acetyl-CoA and acetoacetate; isoleucine into acetyl-CoA and succinyl-CoA; and valine into propionyl-CoA (and subsequently succinyl-CoA). Under fasting conditions, substantial amounts of all three amino acids are generated by protein breakdown. In muscle, the final products of leucine, isoleucine, and valine catabolism can be fully oxidized via the citric acid cycle; in the liver, they can be directed toward the synthesis of ketone bodies (acetoacetate and acetyl-CoA) and glucose (succinyl-CoA). Because isoleucine catabolism terminates with the production of acetyl-CoA and propionyl-CoA, it is both glucogenic and ketogenic. Because leucine gives rise to acetyl-CoA and acetoacetyl-CoA, it is classified as strictly ketogenic.

Pantothenate, also called vitamin B5, is a nutrient that everyone requires in their diet. The nutrient gets its name from the greek word “pantothen” which means “from everywhere.” The reason it is called this is because pantothenic acid is found in almost every food. It is a precursor of coenzyme A, which is an essential part of many reactions in the body, specifically important in the production of compounds like cholesterol and different fatty acids. Most of pantothenic acid is found in food as phosphopentetheine or coenzyme A. Pantothenic acid, pantetheine 4’-phosphate and pantetheine are all found in red blood cells. The 6 step process in which coenzyme A is created begins with the creation of pantothenic acid from pantetheine, which is catalyzed by the enzyme pantetheinase. Pantothenic acid then works with pantothenate kinase 1 to produce D-4’-phosphopantothenate. This compound quickly becomes 4’phosphopantothenoylcysteine through the enzyme phosphopantothenate-cysteine ligase. 4’phosphopantothenoylcysteine then uses phosphopantothenoylcysteine decarboxylase to create pantetheine 4’-phosphate. This compound then undergoes two reactions, both resulting in the production of dephospho-CoA; the first reaction uses ectonucleotide pyrophosphatase/phosphodiesterase family member 1, the second uses bifunctional coenzyme A synthase. In the final step of coenzyme A synthesization, bifunctional coenzyme A synthase catalyzes dephospho-CoA into coenzyme A.

The Spermidine and Spermine Biosynthesis pathway highlights the creation of these cruicial polyamines. Spermidine and spermine are produced in many tissues, as they are involved in the regulation of genetic processes from DNA synthesis to cell migration, proliferation, differentiation and apoptosis. These positiviely charged amines interact with negatively charged phosphates in nucleic acids to exert their regulatory effects on cellular processes. Spermidine originates from the action of spermidine synthase, which converts the methionine derivative S-adenosylmethionine and the ornithine derivative putrescine into spermidine 5'-methylthioadenosine. Spermidine is subsequently processed into spermine by spermine synthase in the presence of the aminopropyl donor, S-adenosylmethioninamine.

Trehalose, also known as mycose or tremalose, is a sugar consisting of two 1-1 alpha bonded glucose molecules. It is produced by some plants, bacteria, fungi and invertebrates, and can be used as a source of energy, such as for flight in insects, and as a survival mechanism to avoid freezing and dehydration. After ingestion in the intestine lumen, trehalose can interact with trehalase, which exists in the brush border of the cells there. In a reaction that also requires a water molecule, it is broken. These are then transported into the epithelial cells along with a sodium ion by a sodium/glucose cotransporter, which can bring glucose up its gradient along with sodium moving down its gradient. Once inside the cell, the glucose can then be transported out of the basolateral membrane by a solute carrier family 2 facilitated glucose transporter. From there, the glucose enters the blood stream, and is transported to liver hepatocytes. Once in the liver, glucokinase can use the energy and phosphate from a molecule of ATP to form glucose-6-phosphate, which then goes on to start the process of glycolysis.

Folates are very important cofactors that provide support for many biosynthetic reactions. The reactions depicted in this pathway include reactions that are paired with transports, within the cell, travelling intracellularly, which allows folate to be absorbed by cells, as well as the synthesis of pterines, which are used in folate synthesis. Two branches are depicted: Pterin synthesis and Folate biosynthesis. In pterin synthesis, GTP is the precursor for pterin biosynthesis. In the first reaction, GTP cyclohydrolase acts to create formamidopyrimidine nucleoside triphosphate from guanosine triphosphate, which is provided from the purine metabolism pathway. Formamidopyrimidine nucleoside triphosphate then uses GTP cyclohydrolase again to create 2,5-diaminopyrimidine nucleoside triphosphate. GTP cyclohydrolase then works with 2,5-diaminopyrimidine nucleoside triphosphate to produce 2,3-diamino-6-(5’-triphosphoryl-3’,4’-trihydroxy-2’-oxopentyl)-amino-4-oxopyrimidine, which is then converted by GTP cyclohydrolase to dihydroneopterin triphosphate. Dihydroneopterin is then transported to the mitochondria and subsequently catalyzed into dyspropterin, which then exits the mitochondria to continue pterin biosynthesis. Once having been transported from the mitochondria, dyspropterin uses sepiapterin reductase, aldose reductase and carbonyl reductase [NADPH] 1 to create 6-lactoyltetrahydropterin. This compound then undergoes 2 reactions, the first being sepiapterin reductase converting 6-lactoyltetrahydropterin into tetrahydrobiopterin, the second being 6-lactoyltetrahydropterin being converted to sepiapterin. Both branches of pterin reactions then respectively end in the creation of neopterin and dihydrobiopterin.

The semi-essential amino aid cysteine is tightly regulated in the body to ensure proper levels for metabolism but maintaining levels below toxic thresholds. Cysteine can be obtained from diet or synthesized from O-acetyl-L-serine. Cystine is the dimeric form of cysteine. Cysteine is a precursor for protein synthesis and an antioxidant. Impaired cysteine metabolism has been linked with neurodegenerative disorders.

Methionine metabolism is a process that is necessary for humans. Methionine metabolism in mammals happens within two pathways, a methionine cycle and a transsulfuration sequence. These pathways have three common reactions with both pathways including the transformation of methionine to S-adenosylmethionine (SAM), the use of SAM in many different transmethylation reactions resulting in a methylated product plus S-adenosylhomocysteine, and the conversion of S-adenosylhomocysteine to produce the compounds homocysteine and adenosine. The reactions mentioned above not only produce cysteine, they also create a-ketobutyrate. This compound is then converted to succinyl-CoA through a three step process after being converted to propionyl-CoA. If the amino acids cysteine and methionine are available in enough quantity, the pathway will accumulate SAM and this will in turn encourage the production of cysteine and a-ketobutyrate, which are both glucogenic, through cystathionine synthase. When there is a lack of methionine, there is a decrease in the production of SAM, which limits cystathionine synthase activity.