Browsing Pathways

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.

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.

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.

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 depicts the metabolic reactions and pathways associated with tryptophan metabolism in animals. Tryptophan is an essential amino acid. This means that it cannot be synthesized by humans and other mammals and therefore must be part of the diet. Unlike animals, plants and microbes can synthesize tryptophan from shikimic acid or anthranilate. As one of the 20 proteogenic amino acids, tryptophan plays an important role in protein biosynthesis through the action of tryptophanyl-tRNA synthetase. As shown in this pathway, tryptophan can be linked to the tryptophanyl-tRNA via either the mitochondrial or cytoplasmic tryptophan tRNA ligases. Also shown in this pathway map is the conversion of tryptophan to serotonin (a neurotransmitter). In this process, tryptophan is acted upon by the enzyme tryptophan hydroxylase, which produces 5-hydroxytryptophan (5HTP). 5HTP is then converted into serotonin (5-HT) via aromatic amino acid decarboxylase. Serotonin, in turn, can be converted into N-acetyl serotonin (via serotonin-N-acetyltransferase) and then melatonin (a neurohormone), via 5-hydroxyindole-O-methyltransferase. The melatonin can be converted into 6-hydroxymelatonin via the action of cytochrome P450s in the endoplasmic reticulum. Serotonin has other fates as well. As depicted in this pathway it can be converted into N-methylserotonin via Indolethylamine-N-methyltransferase (INMT) or it can be converted into formyl-5-hydroxykynurenamine via indoleamine 2,3-dioxygenase. Serotonin may also be converted into 5-methoxyindoleacetate via a series of intermediates including 5-hydroxyindoleacetaldehyde and 5-hydroxyindoleacetic acid. Tryptophan can be converted or broken down into many other compounds as well. It can be converted into tryptamine via the action of aromatic amino acid decarboxylase. The resulting tryptamine can then be converted into indoleacetaldehyde via kynurenine 3-monooxygenase and then into indoleacetic acid via the action of aldehyde dehydrogenase. Tryptophan also leads to the production of a very important compound known as kynurenine. Kynurenine is synthesized via the action of tryptophan 2,3-dioxygnase, which produces N-formylkynurenine. This compound is converted into kynurenine via the enzyme known as kynurenine formamidase (AFMID). Kynurenine has at least 3 fates. First, kynurenine can undergo deamination in a standard transamination reaction yielding kynurenic acid. Secondly, kynurenine can undergo a series of catabolic reactions (involving kynureninase and kynurenine 3-monooxygenase) producing 3-hydroxyanthranilate plus alanine. In this reaction, kynureninase catabolizes the conversion of kynurenine into anthranilic acid while kynurenine—oxoglutarate transaminase (also known as kynurenine aminotransferase or glutamine transaminase K, GTK) catabolizes its conversion into kynurenic acid. The action of kynurenine 3-hydroxylase on kynurenic acid leads to 3-hydroxykynurenine. The oxidation of 3-hydroxyanthranilate converts it into 2-amino-3-carboxymuconic 6-semialdehyde, which has two fates. It can either degrade to form acetoacetate or it can cyclize to form quinolate. Most of the body’s 3-hydroxyanthranilate leads to the production of acetoacetate (a ketone body), which is why tryptophan is also known as a ketogenic amino acid. An important side reaction in the liver involves a non-enzymatic cyclization into quinolate followed by transamination and several rearrangements to yield limited amounts of nicotinic acid, which leads to the production of a small amount of NAD+ and NADP+.

Phosphatidylinositol phosphates, or phosphoinositides, are intracellular signaling lipids. Seven different phosphoinositides have been identified in mammals, each distinguished by the number and/or position of the phosphate groups on the inositol ring. The inositol can be mono-, di-, or triphosphorylated, with the remaining phosphoinositides being isomers of these three forms. Phosphoinositides regulate a variety of signal transduction processes, thus playing a number of important roles in the cell, such as actin cytoskeletal reorganization, membrane transport, and cell proliferation. They may also affect protein localization, aggregation, and activity by acting as secondary messengers. The ability of the cell to recognize the different types of phosphoinositides as different cellular signals means that their synthesis and metabolism must be tightly regulated. Synthesis begins with the attachment of an inositol phosphate head group to diacylglycerol via a phospholipase C enzyme, creating a phosphoinositide. Conversion between the different types of phosphoinositides is then done by a number of specific phosphoinositide kinases and phosphatases, which add (kinase) and remove (phosphatase) phosphates from the inositol ring. The specific localization and regulation of the phosphoinositide kinases and phosphatases thus controls the activity of the phosphoinositides. While the phosphoinositides are always located in the membrane, their particular kinases and phosphatases may be found in the cytoplasm or in the membrane of the cell or cell organelles.

Inositol phosphates are a group of molecules that are important for a number of cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation. Inositol phsosphates consist of an inositol (a sixfold alcohol of cyclohexane) phosphorylated at one or more positions. There are a number of different inositol phosphates found in mammals, distinguishable by the number and position of the phosphate groups. Inositol phosphate can be formed either as a product of phosphatidylinositol phosphate metabolism or from glucose 6-phosphate via the enzyme inositol-3-phosphate synthase 1. Conversion between the different types of inositol phosphates then occurs via a number of specific inositol phosphate kinases and phosphatases, which add (kinase) or remove (phosphatase) phosphate groups. The differing roles of the numerous inositol phosphates means that their metabolism must be tightly regulated. This is done via the localization and activation/deactivation of the various kinases and phosphatases, which can be found in the cytoplasm, nucleus or endoplasmic reticulum. The unphosphorylated inositol ring can be used to produce phosphoinositides through phosphatidylinositol phosphate metabolism.

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.

Betaine (or trimethylglycine) is similar to choline (trimethylaminoethanol) but differs in choline's terminal carboxylic acid group trimethylglycine is reduced to a hydroxyl group. Betaine is obtained from diet as betaine or compounds containing choline in foods such as whole grains, beets and spinach. Betaine can also be synthesized from choline in the liver and kidney. First, choline is oxidized to betaine aldehyde by mitochondrial choline oxidase (choline dehydrogenase). Then, betaine aldehyde dehydrogenase oxidizes betaine aldehyde to betaine in the mitochondria or cytoplasm. In the liver, betaine functions as a methyl donor similar to choline, folic acid, S-adenosyl methionine and vitamin B12. Methyl donors are important for liver function, cellular replication and detoxification reactions. Betaine is also involved in the production of carnitine to protect from kidney damage and functions as an osmoprotectant in the inner medulla.