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Showing 49831 - 49840 of 49833 pathways
SMPDB ID Pathway Chemical Compounds Proteins


Pw125912 View Pathway

Acylcarnitine (2E)-Glutaconylcarnitine

(2E)-Glutaconylcarnitine is an acylcarnitine. The general role of acylcarnitines is to transport acyl-groups, organic acids and fatty acids, from the cytoplasm into the mitochondria so that they can be broken down to produce energy. First,(2E)-glutaconic acid is transported into the cell via the long-chain fatty acid transport protein 1 (FATP1), where it undergoes a reaction to form(2E)-glutaconyl-CoA, facilitated by the Long-chain fatty-acid CoA ligase 1 protein, which adds a CoA to the compound. (2E)-glutaconyl-CoA then enters a reaction with L-carnitine, which is transported into the cell by the organic cation/carnitine transporter 2, to form (2E)-glutaconylcarnitine, catalyzed by carnitine O-palmitoyltransferase. This enzyme resides in the mitochondrial outer membrane, and as the reaction takes place, the (2E)-glutaconylcarnitine is moved into the mitochondrial intermembrane space. Following the reaction, (2E)-glutaconylcarnitine is transported into the mitochondrial matrix by a mitochondrial carnitine/acylcarnitine carrier protein found in the mitochondrial inner membrane. Once in the matrix, (2E)-glutaconylcarnitine and CoA are catalyzed by the carnitine O-palmitoyltransferase 2 enzyme found in the mitochondrial inner membrane to once again form (2E)-glutaconyl-CoA and L-carnitine. (2E)-Glutaconyl-CoA then enters into mitochondrial beta-oxidation to form aceytl-CoA. Acetyl-CoA can go on to enter the TCA cycle, or it can react with L-carnitine to form L-acetylcarnitine and CoA in a reaction catalyzed by Carnitine O-acetyltransferase. This reaction can occur in both directions, and L-acetylcarnitine and CoA can react to form acetyl-CoA and L-carnitine in certain circumstances. Finally, acetyl-CoA in the cytosol can be catalyzed by acetyl-CoA carboxylase 1 to form malonyl-CoA, which inhibits the action of carnitine O-palmitoyltransferase 1, preventing (2E)-glutaconyl-CoA from forming (2E)-glutaconylcarnitine and preventing it from being transported into the mitochondria. Malonyl-CoA can also react to form acetyl-CoA, in a reaction that removes a carbon dioxide molecule catalyzed by malonyl-CoA decarboxylase.


Pw126201 View Pathway

1-Methylhistidine Metabolism

Methylhistidine is a modified amino acid that is produced in myocytes during the methylation of actin and myosin. It is also formed from the methylation of L-histidine, which takes the methyl group from S-adenosylmethionine and forms S-adenosylhomocysteine as a byproduct. After its formation in the myocytes, methylhistidine enters the blood stream and travels to the kidneys, where it is excreted in the urine. Methylhistidine is present in the blood and urine in higher concentrations after skeletal muscle protein breakdown, which can occur due to disease or injury. Because of this, it can be used to judge how much muscle breakdown is occurring. Methylhistidine levels are also affected by diet, and may differ between vegetarian diets and those containing meats.


Pw127040 View Pathway

Immunometabolism Pathway (Bacterial Activation)

The normal response to a bacterial infection involves bacteria activateing the Toll-like receptor TLR4 on the membranes of macrophages, T-cells and dendritic cells. TLR4 activates the production of interferon regulatory factor 3 (IRF3), TIR-domain-containing adapter-inducing interferon-β (TRIF), signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NF-kB) in the cytoplasm [1]. The NF-kB protein then goes to nucleus and activates expression of nitric oxide synthase (iNOS) which generates nitric oxide (NO). It also activates aconitate decarboxylase (Irg1), tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β). These are the pro-inflammatory proteins while nitric oxide (NO) is also a pro-inflammatory molecule that can lead to the production of oxidized tyrosines (i.e., nitrotyrosine). Similarly, the newly expressed IRF3 goes to the nucleus and activates the production of interferon beta (IFN- β), which is another pro-inflammatory cytokine. The whole collection of cytokines, TNF, IL-6, IL-1β and IFN-β move into the bloodstream and head to the brain and into the hypothalamus, leading to release of the hypothalamic corticotropin releasing hormone (CRH) [2]. CRH, in turn, activates the release of pituitary adrenocorticotropic hormone (ACTH), which then moves down through the blood stream towards the adrenal glands (located at the top of the kidneys) to produce cortisol and epinephrine. Cortisol and epinephrine stimulate the ”flight or fight” response, leading to the increased production of glucose from the liver (via glycogen breakdown) and the release of short-chain acylcarnitines (also from the liver) to help support beta-oxidation of fatty acids. These compounds support cell synthesis and growth of the macrophages and neutrophils used in the innate immune response. The liver also produces more IL-6, more TNF and more NO to further stimulate the innate immune response. Higher nitric oxide (NO) levels lead to blood vessel dilation and reduced blood pressure, which in its most extreme form, can be a major problem in sepsis. Higher iNOS expression in macrophages, neutrophils and dendritic cells consumes the amino acid arginine to produce more NO which disrupts the mitochondrial TCA cycle leading to the accumulation of citrate and the production of fatty acids and acylcarnitines (needed for lipid synthesis). Increased Irg1 (actonitate decarboxylase) expression leads to accumulation of succinate, which results in the succinylation of phosphofructokinase M2 (PKM2) [3]. Succinate also leads to the release of hypoxia inducible factor 1-alpha (HIF-1α) from its PHD-mediated inhibition. HIF-1α interacts with succinylated PKM2 and induces the expression of glycolytic genes such as Glut1 (the glucose transporter) and the pro-inflammatory cytokine IL-1β [3]. As a result of these metabolic changes and the deactivation of the oxidative phosphorylation pathway in their mitochondria, macrophages, neutrophils, T-cells and dendritic cells shift to aerobic glycolysis [4]. This leads to the production of more reactive oxygen species (ROS) which results in the oxidation of certain amino acids, such as methionine. This leads to the increased production of methionine sulfoxide (Met-SO). As the inflammatory response continues, more glucose and arginine in the bloodstream are consumed by dividing white blood cells to produce more lactate and more NO to further push the aerobic glycolytic pathway [4]. This aerobic glycolysis occurs primarily in white blood cells leading to active cell division and rapid white cell propagation (growing by a factor of three to four in a few hours). Hexokinase (HK) along with increased levels of lactate from aerobic glycolysis activate the inflammasome inside macrophages and dendritic cells, leading to the secretion of IL-1β. This cytokine further drives the aerobic glycolysis pathway for these white blood cells. All these signals and effects combine to lead to the rapid and sustained production of large numbers of macrophages, neutrophils, dendritic cells and T-cells to fight the bacterial infection. This often leads to a reduction in essential amino acids (threonine, lysine, tryptophan, leucine, isoleucine, valine, arginine) and a mild reduction in gluconeogenic acids (glycine, serine) in the bloodstram. The reduction in essential amino acids is intended to “starve” the invading bacteria (and other pathogens) of the amino acids they need to reproduce [4]. Some of the reduction in amino acid levels is moderated by the proteolysis of myosin in the muscle and the proteolysis of serum albumin in the blood (the most abundant protein in the blood, which is produced by the liver). These proteins act as amino acid reservoirs to help support rapid immune cell production. The loss of serum albumin in the blood to help support amino acid synthesis elsewhere can lead to hypoalbuminemia, a common feature of infections and inflammation. As the bacteria are cleared, the body goes into the anti-inflammatory response.
Showing 49831 - 49840 of 49833 pathways