Browsing Pathways

The distal convoluted tubule of the nephron is the part of the kidney between the loop of henle and the collecting duct. When renin is released from the kidneys, it causes the activation of angiotensin I in the blood circulation which is cleaved to become angiotensin II. Angiotensin II stimulates the release of aldosterone from the adrenal cortex and release of vasopressin from the posterior pituitary gland. When in the circulation, vasopressin eventually binds to receptors on epithelial cells in the distal convoluted tubule. This causes vesicles that contain aquaporins to fuse with the plasma membrane. Aquaporins are proteins that act as water channels once they have bound to the plasma membrane. As a result, the permeability of the distal convoluted tubule changes to allow for water reabsorption back into the blood circulation. In addition, sodium, chlorine, and calcium are also reabsorbed back into the systemic circulation via their respective channels and exchangers. However, aldosterone is a major regulator of the reabsorption of these ions as well, as it changes the permeability of the distal convoluted tubule to these ions. As a result, a high concentration of sodium, chlorine, and calcium in the blood vessels occurs. The reabsorption of ions and water increases blood fluid volume and blood pressure.

Pancreatic delta cells produce somatostatin which functions to inhibit glucagon, insulin, and itself. Somatostatin is stored in granules in the delta cell and is released in response to an increase in blood sugar, calcium, and blood amino acids during absorption of a meal. In the process of somatostatin secretion, glucose must first undergo glycolysis in the mitochondrion to increase ATP in the cell. The inside of the alpha cell then becomes electrically positive due to the closure of potassium channels that were inhibited by ATP. From this closure, the potassium is no longer being shuttled out of the cell, thus depolarizing the cell due to the extra intracellular potassium. The resulting action potential from the increased membrane potential causes the voltage gate calcium channels to open, creating an influx of calcium into the cell. This triggers the exocytosis of somatostatin granules from the delta cell.

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.

In the majority of organisms, fatty acid degradation occurs mostly through the beta-oxidation cycle. In plants, this cycle only happens in the peroxisome, while in mammals this cycle happens in both the peroxisomes and mitochondria. Unfortunately, traditional fatty acid oxidation does not work for branched-chain fatty acids, or fatty acids that do not have an even number of carbons, like the fatty acid phytanic acid, found in animal milk. This acid can not be oxidized through beta-oxidation, as problems arise when water is added at the branched beta-carbon. To be able to oxidize this fatty acid, the carbon is oxidized by oxygen, which removes the initial carboxyl group, which shortens the chain. Now lacking a methyl group, this chain can be beta-oxidized. Now moving to the mitochondria, there are four reactions that occur, and are repeated for each molecule of the fatty acid. Each time the cycle of these reactions is completed, the chain is relieved of two carbons, which are oxidized and are taken away by NADH and FADH2, energy carriers that collect the carbons energy. After beta-oxidation in the cycle of reactions, an acetyl-CoA unit is released and is recycled into the cycle of reactions in the mitochondria, until the chain is fully broken down into acetyl-CoA, and can enter the TCA cycle. Once in the TCA cycle, it is converted to NADH and FADH2, which in turn help move along mitochondrial ATP production. Acetyl-CoA also helps produce ketone bodies that are further converted to energy in the heart and the brain.

The malate-aspartate shuttle system, also called the malate shuttle, is an essential system used by mitochondria, that allows electrons to move across the impermeable membrane between the cytosol and the mitochondrial matrix. The electrons are created during glycolysis, and are needed for oxidative phosphorylation. The malate-aspartate shuttle is needed as the inner membrane is not permeable to NADH or NAD+, but is permeable to the ions that attach to malate. When the malate gets inside the membrane,the energy inside of malate is taken out by creating NADH from NAD+, which regenerates oxaloacetate. NADH can then transfer electrons to the electron transport chain.

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.

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.

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.

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.