Browsing Pathways

Plasmalogens are a class of phospholipids found in animals. Plasmalogens are thought to influence membrane dynamics and fatty acid levels, while also having roles in intracellular signalling and as antioxidants. Plasmalogens consist of a glycerol backbone with an vinyl-ether-linked alkyl chain at the sn-1 position, an ester-linked long-chain fatty acid at the sn-2 position, and a head group attached to the sn-3 position through a phosphodiester linkage. It is the vinyl-ether-linkage that separates plasmalogens from other phospholipids. Plasmalogen biosynthesis begins in the peroxisomes, where the integral membrane protein dihydroxyacetone phosphate acyltransferase (DHAPAT) catalyzes the esterification of the free hydroxyl group of dihydroxyacetone phosphate (DHAP) with a molecule any of long chain acyl CoA. Next, alkyl-DHAP synthase, a peroxisomal enzyme associated with DHAPAT, replaces the fatty acid on the DHAP with a long chain fatty alcohol. The third step of plasmalogen biosynthesis is catalyzed by the enzyme acyl/alkyl-DHAP reductase, which is found in the membrane of both the peroxisome and endoplasmic reticulum (ER). Acyl/alkyl-DHAP reductase uses NADPH as a cofactor to reduce the ketone of the 1-alkyl-DHAP using a classical hydride transfer mechanism. The remainder of plasmalogen synthesis occurs using enzymes in the ER. Lysophosphatidate acyltransferases (LPA-ATs) transfer the acyl component of a polyunsaturated acyl-CoA to the the 1-alkyl-DHAP, creating a 1-alkyl-2-acylglycerol 3-phosphate. The phosphate is then removed by lipid phosphate phosphohydrolase I (PAP-I), and the head group is attached by a choline/ethanolaminephosphotransferase. The majority of plasmalogens have either ethanolamine or choline as a headgroup, although a small amount of serine and inositol-linked ether-phospholipids can also be found. In the final step, the vinyl-ether linkage is created by plasmanylethanolamine desaturase, which catalyzes the formation of a double bond in the alkyl chain of the plasmalogen.

The proximal convoluted tubule is part of the nephron between the Bowman's capsule and the loop of Henle. The proximal convoluted tubule functions to reabsorb sodium, water, and other ions. Sodium and bicarbonate (hydrogen carbonate) are transported by a co-transporter that is responsible for the majority of sodium reabsorption. The bicarbonate, along with hydrogen, are exchanged across the basal and apical membranes, respectively, to effectively regulate the pH of the filtrate. In addition, chloride ions are not normally reabsorbed in large amounts at the proximal tubule compared to other parts of the nephron. However, the reabsorption of chloride, as well as potassium, increases as the amount of water reabsorption increases due to solvent drag (also known as bulk transport). This occurrence explains solute movement secondary to water flow. All the cation and anion transport creates a gradient favourable for ion and water reabsorption, leading to an increase in blood pressure.

The transcription of DNA is aided in large part by something called "homeodomain transcription factors". They are a diverse group of DNA binding factors. In fact, genes which are created with the aid of homeodomain factors tend to conglomerate and are responsible for anterior-posterior patterning. There is much to be said as well regarding the development and growth of cardiac myocytes and homedomain transcription factors. Indeed, at the early stages of the cell differentiation of cardiac myoctes a delicate balance of joint expression of several factors is needed for correct development (namely: serum response factor (SRF), and GATA4) and a homeodomain factor known as Nkx2-5! The joint expression of the aforementioned factors is the critical in the development of myocytes as well as gene expression in the cardiac region. To underline the importance of the homeodomain transcription factors, note that an error in the Nkx2-5 gene has severe consequences, which include, though are not necessarily limited to, embryonic lethality, as well as severe problems in general heart development. To put all this in context of the pathway in question, Hop actually stands for (Homeodomain Only Protein). The Hop gene plays an important role in the cardiac development we have been describing, as it too encodes a homedomain factor which plays an important role at the onset stages of cardiac development. The Hop gene is downstream of the Mkx2-5 factor we discussed earlier, and similar to it, improper activation of Hop can lead to severe cardiac development issues. In mice for example, not have the Hop gene results in alterations to the cell cycle. In particular, cardiac cells are unable to exit the cycle at the correct stage and continue grow after normal developmental stage has finished. There exists an interesting symbiosis between Hop and SRF. First, Hop regulates gene expression by either binding to SRF or by preventing SRF binding to DNA. This occurs because Hop does not have anything to bind to DNA with, and as such must have different methods to regulate gene expression. Second, when Hop blocks normal SRF binding, the results is that the activation of genes in the heart is affected and normal development does not occur. In a nutshell, what can be said about this tango action of SRF and Hop is this: during the first stages of development, what is observed is that the Hop interaction is one which results in a cessation of the differentiation processes which are induced by SRF. In the later stages, it appears that Hop reduces cell proliferation which is normally caused by SRF.

This pathway describes the synthesis and breakdown of several small amino acids, including glycine, serine, and cysteine. All of these compounds share common intermediates and almost all can be biosynthesized from one another. Serine and glycine are not essential amino acids and can be synthesized from several routes. On the other hand, cysteine is a conditionally essential amino acid, meaning that it can be endogenously synthesized but insufficient quantities may be produced due to certain diseases or conditions. Serine is central to the synthesis and breakdown of the other two amino acids. Serine can be synthesized via glycerate, which can be converted into glycerate 3-phosphate (via glycerate kinase), which in turn is converted into phosphohydroxypyruvate by phosphoglycerate dehydrogenase and then phosphoserine (via phosphoserine transaminase) and finally to serine (via phosphoserine phosphatase). The serine synthesized via this route can be used to create cysteine and glycine through the homocysteine cycle. In the homocysteine cycle, cystathionine beta-synthase catalyzes the condensation of homocysteine and serine to give cystathionine. Cystathionine beta-lyase then converts this double amino acid to cysteine, ammonia, and alpha-ketoglutarate. Glycine is biosynthesized in the body from the amino acid serine. In most organisms, the enzyme serine hydroxymethyltransferase (SHMT) catalyzes this transformation using tetrahydrofolate (THF), leading to methylene THF and glycine. Glycine can be degraded via three pathways. The predominant pathway in animals involves the glycine cleavage system, also known as the glycine decarboxylase complex or GDC. This system is usually triggered in response to high concentrations of glycine. The system is sometimes referred to as glycine synthase when it runs in the reverse direction to produce glycine. The glycine cleavage system consists of four weakly interacting proteins: T, P, L and H-proteins. The glycine cleavage system leads to the degradation of glycine into ammonia and CO2. In the second pathway, glycine is degraded in two steps. The first step in this degradation pathway is the reverse of glycine biosynthesis from serine with serine hydroxymethyltransferase (SHMT). The serine generated via glycine is then converted into pyruvate by the enzyme known as serine dehydratase. In the third route to glycine degradation, glycine is converted into glyoxylate by D-amino acid oxidase. Glyoxylate is then oxidized by hepatic lactate dehydrogenase into oxalate in an NAD+-dependent reaction.

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.

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.

Linoleic acid (LNA) is a polyunsaturated fatty acid (PUFA) precursor to the longer n−6 fatty acids commonly known as omega-6 fatty acids. Omega-6 fatty acids are characterized by a carbon-carbon double bond at the sixth carbon from the methyl group. Similarly, the PUFA alpha-linoleic acid (ALA) is the precursor to n-3 fatty acids known as omega-3 fatty acids which is characterized by a carbon-carbon double bond at the third carbon from the methyl group. Both LNA and ALA are essential dietary requirements for all mammals since they cannot be synthesized natively in the body. Both undergo a series of similar conversions to reach their final fatty acid form. LNA enters the cell and is catalyzed to gamma-linolenic acid (GLA) by acyl-CoA 6-desaturase (delta-6-desaturase/fatty acid desaturase 2). GLA is then converted to dihomo-gammalinolenic acid (DGLA) by elongation of very long chain fatty acids protein 5 (ELOVL5). DGLA is then converted to arachidonic acid (AA) by acyl-CoA (8-3)-desaturase (delta-5-desaturase/fatty acid desaturase 1). Arachidonic acid is then converted to a series of short lived metabolites called eicosanoids before finally reaching it's final fatty acid form.

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.

Gluconeogenesis, which is essentially the reverse of glycolysis, results in the sythesis of glucose from non-carbohydrate substrates such as lactate, glycerol, and glucogenic amino acids. In animals, gluconeogenesis occurs primarily in the liver, and in the renal cortex to a lesser extent. This process occurs during periods of fasting or intense exercise. Gluconeogenesis is often associated with ketosis. Several non-carbohydrate carbon substrates can enter the gluconeogenesis pathway. One common substrate is lactic acid, formed during anaerobic respiration in skeletal muscle. Lactate may also come from red blood cells, which obtain energy solely from glycolysis as they have no membrane-bound organelles for aerobic respiration. Lactate is transported to the liver to be converted into pyruvate in the Cori cycle by lactate dehydrogenase. Pyruvate can then be used to generate glucose via gluconeogenesis. Many other compounds can also function as substrates for gluconeogenesis such as citric acid cycle intermediates (through conversion to oxaloacetate), amino acids other than lysine or leucine, and glycerol .

Lactose synthesis occurs only in the mammary glands, producing lactose (4-O-B-D-galactosylpyranosyl-a-D-glucopyranoside), the major sugar in milk. Lactose is created by joining two monosaccarides with a B1,4 glycosidic bond. Glucose is first converted to UDP-galactose via the enzyme galactose-1-phosphate uridylyltransferase. UDP-galactose is then transported into the Golgi by the UDP galactose translocator, an antiporter which uses facilitated transport to move UDP galactose into the Golgi and exports UMP. Once inside the Golgi, the UDP galactose and glucose (which moves into the golgi via the GLUT-1 transporter) become substrates for the lactose synthase enzyme complex, comprised of the enzymatic subunit, galactosyltransferase with its regulatory subunit, Alpha-lactalbumin. Lactose synthase creates lactose through bonding galactose from UDP to glucose through a glycosidic bond. Although GT is found in many tissues in the body, Alpha-lactalbumin is only found on the inner surface of the Golgi in the mammary glands, limiting lactose production to the mammaries.