Browsing Pathways

Beta-oxidation is the major degradative pathway for fatty acid esters in humans. Fatty acids and their CoA esters are found throughout the body, playing roles such as components of cellular lipids, regulators of enzymes and membrane channels, ligands for nuclear receptors, precursor molecules for hormones, and signalling molecules. Beta-oxidation occurs in the peroxisomes and mitochondria, the latter of which is depicted here. Whether beta-oxidation starts in the mitochondria or the peroxisome depends on the length of the fatty acid. Medium to long chain fatty acids go directly to the mitochondria, whereas very long chain fatty acids (>22 carbons) may be first metabolized down to octanyl-CoA in the peroxisomes and then transported to the mitochondria for the remainder of the oxidation. Beta-oxidation begins with fatty acids first being activated by an acyl-coenzyme A synthetase. This process uses ATP to produce a reactive fatty acyl adenylate which then reacts with coenzyme A to produce a fatty acyl-CoA. Short and medium chain fatty acids can enter the mitochondria directly via diffusion where they are activated in the mitochondrial matrix by acyl-coenzyme A synthetases. Long chain fatty acids must be activated in the outer mitochondrial membrane then transported as a carnatine complex into the mitochondria. A double bond is formed between C-2 and C-3 to produce trans-Δ2-enoyl-CoA which is catalyzed by acyl-CoA-dehydrogenases in the mitochondria. Enoyl CoA hydratase then hydrates the double bond between C-2 and C-3 to produce a L-beta-hydroxyacyl CoA which then has its hydroxyl group converted to a keto group to produce beta-ketoacyl CoA. Finally, the beta-ketoacyl CoA is cleaved by beta-ketothiolase and a thiol group is inserted between C-2 and C-3 to reduce the acyl-CoA and produce acetyl-CoA. Acetyl-CoA can then enter the citric acid cycle.

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.

Neurons are electrically excitable cells that process and transmit information through electrical and chemical signals. A neuron consists of a cell body, branched dendrites to receive sensory information, and a long singular axon to transmit motor information. Signals travel from the axon of one neuron to the dendrite of another via a synapse. Neurons maintain a voltage gradient across their membrane using metabolically driven ion pumps and ion channels for charge-carrying ions, including sodium (Na+), potassium (K+), chloride (Cl−), and calcium (Ca2+). The resting membrane potential (charge) of a neuron is about -70 mV because there is an accumulation of more sodium ions outside the neuron compared to the number of potassium ions inside. If the membrane potential changes by a large enough amount, an electrochemical pulse called an action potential is generated. Stimuli such as pressure, stretch, and chemical transmitters can activate a neuron by causing specific ion-channels to open, changing the membrane potential. During this period, called depolarization, the sodium channels open to allow sodium to rush into the cell which results in the membrane potential to increase. Once the interior of the neuron becomes more positively charged, the sodium channels close and the potassium channels open to allow potassium to move out of the cell to try and restore the resting membrane potential (this stage is called repolarization). There is a period of hyperpolarization after this step because the potassium channels are slow to close, thus allowing more potassium outside the cell than necessary. The resting potential is restored after the sodium-potassium pump works to exchange three sodium ions out per two potassium ions in across the plasma membrane. The action potential travels along the axon and upon reaching the end, causes neurotransmitters such as serotonin, dopamine, or norepinephrine to be released into the synapse. These neurotransmitters diffuse across the synapse and bind to receptors on the target cell, thus propagating the signal.

Angiotensin is a peptide hormone that is part of the renin-angiotensin system responsible for regulating fluid homeostasis and blood pressure. It is involved in various means to increase the body's blood pressure, hence why it is a target for many pharmceutical drugs that treat hypertension and cardiac conditions. Angiotensin II, the primary agent to inducing an increased blood pressure, is formed in the general circulation when it is cleaved from a string of precursor molecules. Angiotensinogen is converted into angiotensin I with the action of renin, an enzyme secreted from the kidneys. From there, angiotensin I is converted to the central agent, angiotensin II, with the aid of angiotensin-converting enzyme (ACE) so that it is available in the circulation to act on numerous areas in the body when an increase in blood pressure is needed. Angiotensin II can act directly on receptors on the smooth muscle cells of the tunica media layer in the blood vessel to induce vasoconstriction and a subsequent increase in blood pressure. However, it can also influence the blood pressure by aiding in an increase of the circulating blood volume. Angiotensin II can cause vasopressin to be released, which is a hormone involved in regulating water reabsorption. Vasopressin is created in the supraoptic nuclei and they travel down the neurosecretory neuron axon to be stored in the neuronal terminals within the posterior pituitary. Angiotensin II in the cerebral circulation triggers the release of vasopressin from the posterior pituitary gland. From there, vasopressin enters into the systemic blood circulation where it eventually binds to receptors on epithelial cells in the collecting ducts of the nephron. The binding of vasopressin causes vesicles of epithelial cells to fuse with the plasma membrane. These vesicles contain aquaporin II, which are proteins that act as water channels once they have bound to the plasma membrane. As a result, the permeability of the collecting duct changes to allow for water reabsorption back into the blood circulation. Angiotensin II also has an effect on the hypothalmus, where it helps trigger a thirst sensation. Correspondingly, there will be an increase in oral water uptake into the body, which would then also increase the circulating blood volume. Another way that angiotensin II helps increase the blood volume is by acting on the adrenal cortex to stimulate aldosterone release, which is responsible for increasing sodium reuptake in the distal convoluted tubules and the collecting duct. It is formed when angiotensin II binds to receptors on the zona glomerulosa cells in the adrenal cortex, which triggers a signaling cascade that eventually activates the steroidogenic acute regulatory (StAR) protein to allow for cholesterol uptake into the mitochondria. Cholesterol then undergoes a series of reactions during steroidogenesis, which is a process that ultimately leads to the synthesis of aldosterone from cholesterol. Aldosterone then goes to act on the distal convoluted tubule and the collecting duct to make them more permeable to sodium to allow for its reuptake. Water subsequently follows sodium back into the system, which would therefore increase the circulating blood volume. In addition, potassium and hydrogen are also being excreted into the urine simultaneously to maintain the electrolyte balance.

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.

Reactive oxygen species (ROS) are formed by the normal metabolic process of oxygen. Examples are superoxide, oxygen ions and peroxides and can be of either organic or inorganic origin. ROS are highly reactive due to unpaired valence shell electrons, and can cause serious damage to cells and cell organelles. The environment also may cause ROS to form, from sources such as drought, air pollutants, UV light, cold temperatures, and external chemicals. An organic example of ROS being formed is during the beta oxidation of fatty acids, or photorespiration in photosynthetic organisms. Aerobic organisms who produce energy through the electron transport chain in mitochondria produce ROS as a byproduct. ROS damage commmonly includes DNA damage, lipid peroxidation, oxidation of amino acids in proteins, and oxidatively inactivating enzymes by oxidation of cofactors. Most aerobic organisms have adapted to this dangerous condition of life, and have a system of enzymes and scavenging free radicals. Enzymes such as are essential for defense against ROS, and include superoxide dismutases (SODs) and hydroperoxidase (CAT). Superoxide dismutases are the primary method of disposal of ROS, and convert superoxide radicals to hydrogen peroxide and water. Catalase attacks the hydrogen peroxide produced by SODs, and converts it into oxygen and water. In skin cells, 5,6 dihydroxyindole-2-carboxylic acid oxidase in the melanosome membranes breaks down hydrogen peroxide into water and oxygen.

Arsenate is a compound similar to phosphate, but containing an arsenic atom instead of the phosphorous. As such, it is treated similarly to a phosphate ion. However, if the arsenate replaces inorganic phosphates in glycolysis, it allows glycolysis to proceed, but does not generate ATP, uncoupling glycolysis. It can also bind to lipoic acid in the Krebs cycle, leading to a greater loss of ATP. Arsenate can enter into the cell via aquaporins 7 and 9, as well as facilitated glucose transporter members 1 and 4 of solute carrier family 2, and does so by diffusion. Once inside the cell, the arsenate can be converted to arsenite via the glutathione S-transferase omega-1 enzyme, or it can be converted to ribose-1-arsenate via the purine nucleoside phosphorylase. Ribose-1-arsenate then can spontaneously form arsenite through a reaction involving hydrogen and dihydrolipoate. After arsenite has been formed by either of these methods, arsenite methyltransferase catalyzes its formation into methylarsonate. From here, it forms methylarsonite via the glutathione S-transferase omega-1 enzyme again. The methylarsonite reacts with S-adenosylmethionine, catalyzed by arsenite methyltransferase, in order to become dimethylarsinate. Finally, the compound once again interacts with the glutathione S-transferase omega-1 enzyme to form dimethylarsinous acid, the final compound in this pathway.

Aldosterone is a hormone produced in the zona glomerulosa of the adrenal cortex. It's function is to act on the distal convoluted tubule and the collecting duct of the nephron to make them more permeable to sodium to allow for its reuptake (in addition to allowing potassium wasting). As a result, water follows the sodium back into the body. The water retention contributes to an increased blood volume. Angiotensin II from the circulation binds to receptors on the zona glomerulosa cell membrane, activating the G protein and triggering a signaling cascade. The end result is the activation of the steroidogenic acute regulatory (StAR) protein that permits cholesterol uptake into the mitochondria. From there, cholesterol undergoes a series of reactions in both the mitochondrion and the smooth endoplasmic reticulum (steroidogenesis) where it finally becomes aldosterone.

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.

This pathway is part of a major route of the degradation of L-tryptophan. It begins with 2-amino-3-carboxymuconate-6-semialdehyde which is generated from L-tryptophan degradation. The 2-amino-3-carboxymuconate-6-semialdehyde first is acted upon by a decarboxylase, forming 2-aminomuconic acid semialdehyde, which is then dehydrogenated by 2-aminomuconic semialdehyde dehydrogenase to form 2-aminomuconic acid. An unknown protein forms a 2-aminomuconate deaminase which forms (3E)-2-oxohex-3-enedioate, and a second unknown protein forms a 2-aminomuconate reductase, which forms oxoadipic acid from (3E)-2-oxohex-3-enedioate. Finally, within the mitochondria, oxoadipic acid is dehydrogenated and a coenzyme A is attached by the organelle’s oxoglutarate dehydrogenase complex, forming glutaryl-CoA. Glutaryl-CoA can then be further degraded.