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 activation of fatty acids by an acyl-coenzyme A synthetase. ATP is used to produce reactive fatty acyl adenylate that can then react 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. In the first step of the beta-oxidation cycle, a double bond between C-2 and C-3 is formed, producing a trans-Δ2-enoyl-CoA. This is catalyzed by acyl-CoA-dehydrogenases in the mitochondria, which have forms specific to the different lengths of fatty acids. In the second step, enoyl CoA hydratase hydrates the newly formed double bond between C-2 and C-3, producing an L-beta-hydroxyacyl CoA. Next, L-beta-hydroxyacyl CoA dehydrogenase converts the hydroxyl group into a keto group, producing a beta-ketoacyl CoA. In the fourth and final step, the enzyme beta-ketothiolase cleaves the β-ketoacyl CoA and inserts the thiol group of another CoA between C-2 and C-3, reducing the acyl-CoA by 2 carbons and generating acetyl-CoA. The final two steps also have enzymatic forms specific to short chain fatty acids. Additionally, there is a trifunctional protein complex with enzymatic activity capable of performing all of the final 3 steps (hydratase, dehydrogenase, thiolase) in medium to very long chain fatty acids. This four step cycle repeats, removing 2 carbons from the fatty acid each time until it becomes acetyl-CoA. Acetyl-CoA is necessary for the citric acid cycle, among other cellular processes.

Alpha cells are a type of islet cell found in the pancreas that release glucagon. Glucagon counteracts insulin and functions to maintain glucose homeostasis when detected glucose levels are low. Glucagon is contained in granules in the cell as a reserve ready to be released. Extracellular glucose levels and ion channels regulate the secretion of glucagon. Glucose undergoes glycolysis to increase ATP in the cell. The moderate activity of potassium ATP channels causes the membrane potential to be around -70mV. The alpha cell then becomes electrically active due to the closure of potassium channels. The cell membrane becomes depolarized due to voltage dependent sodium, potassium and calcium channels. This causes an increase in action potentials and opens voltage gate calcium channels causing an increase of calcium into the cell. This triggers the exocytosis of glucagon from the cell. Conversely, an increase in extracellular glucose leads to an increase in ATP production and inhibition of potassium ATP channels. The membrane depolarizes to a membrane potential that inactivates voltage dependent calcium channels. This results in decreased intracellular calcium and inhibits exocytosis of glucagon.

The loop of Henle of the nephron can be separated into an ascending limb and the descending limb. The descending limb is highly impermeable to solutes such as sodium, but permeable to water. Conversely, the ascending limb is highly impermeable to water, but permeable to solutes. Chloride, potassium, and sodium are co-transported across the apical membrane (closest to the lumen) via transporters from the filtrate. The transporter requires all three ions present to be effective and to maintain electroneutrality. In addition, the three ions are transported across the basolateral membrane (closest to the renal interstitium) via other means such as the sodium potassium ATPase transports and the chloride channels in the membrane. As these solutes are being actively transported out of the ascending limb and into the renal interstitium/capillary network without water following (due to the lack of water permeability), the filtrate becomes more diluted. Furthermore, these ions simultaneously causes an increase in osmotic pressure that contributes to water reabsorption in the descending limb. This effect can be magnified with the help of vasopressin, which is a hormone that is typically involved with water reabsorption. However, when it acts on the ascending limb, it aids in increasing sodium reabsorption which will increase water reabsorption in the latter parts of the nephron (the distal tubule and collecting duct).

Phospholipids are membrane components in P. aeruginosa. The major phospholipids of P. aeruginosa are phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. All phospholipids contain sn-glycerol-3-phosphate esterified with fatty acids at the sn-1 and sn-2 positions. The reaction starts from a glycerone phosphate (dihydroxyacetone phosphate) produced in glycolysis. The glycerone phosphate is transformed into an sn-glycerol 3-phosphate (glycerol 3 phosphate) by NADPH-driven glycerol-3-phosphate dehydrogenase. sn-Glycerol 3-phosphate is transformed to a 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid). This can be achieved by an sn-glycerol-3-phosphate acyltransferase that interacts either with a long-chain acyl-CoA or with an acyl-[acp]. The 1-acyl-sn-glycerol 3-phosphate is transformed into a 1,2-diacyl-sn-glycerol 3-phosphate (phosphatidic acid) through a 1-acylglycerol-3-phosphate O-acyltransferase. This compound is then converted into a CPD-diacylglycerol through a CTP phosphatidate cytididyltransferase. CPD-diacylglycerol can be transformed either into an L-1-phosphatidylserine or an L-1-phosphatidylglycerol-phosphate through a phosphatidylserine synthase or a phosphatidylglycerophosphate synthase, respectively. The L-1-phosphatidylserine transforms into L-1-phosphatidylethanolamine through a phosphatidylserine decarboxylase. On the other hand, L-1-phosphatidylglycerol-phosphate gets transformed into an L-1-phosphatidyl-glycerol through a phosphatidylglycerophosphatase. These 2 products combine to produce a cardiolipin and an ethanolamine. The L-1 phosphatidyl-glycerol can also interact with cardiolipin synthase resulting in a glycerol and a cardiolipin.

Phenylacetate (or phenylacetic acid) metabolism involves two steps. The first step is the conversion of phenylacetate into phenylacetyl-CoA which is catalyzed by acyl-coenzyme A synthetase ACSM1 or acyl-coenzyme A synthetase ACSM2B. Coenzyme A and ATP are also involved in this first step and AMP and pyrophosphate will be generated during the first step of metabolism. In the second step, phenylacetyl-CoA and L-glutamine interacts with glycine N-acyltransferase to generate coenzyme A as well as phenylacetylglutamine, of which the latter will be excreted in the urine. Phenylacetate metabolism provides a route that facilitates the excretion of nitrogen for patients with urea cycle defects; hence, it is important for clinical purposes.

D-Amino acids have been show to be present in high concentrations in humans and play a role in biological functions. D-Amino may have negative effects as they can be found in some bacteria or form spontaneously in certain reactions. D-Amino acid oxidase (DAAO) is one of the main enzymes that metabolize D-Amino acids via deamination. DAAO is highly specific towards D-amino acids and favours free neutral D-amino acids or those with hydrophobic, polar or aromatic groups. Acidic amino acids are not catalyze by DAOO.

Butyrate metabolism (Butanoate metabolism) describes the metabolic fate of a number of short chain fatty acids or short chain alcohols that are typically produced by intestinal fermentation. Many of these molecules are eventually used in the production of ketone bodies, the creation of short-chain lipids or as precursors to the citrate cycle, glycolysis or glutamate synthesis. The molecule for which this pathway is named, butyric acid, is a four-carbon fatty acid that is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber). It is found in rancid butter, parmesan cheese, and vomit, and has an unpleasant odor and acrid taste, with a sweet aftertaste (similar to ether).

Steroidogenesis is a process that through the transformations of other steroids, produces a desired steroid. Some of these desired steroids include cortisol, corticoids, testosterone, estrogens, aldosterone and progesterone. To begin the synthesis of steroid hormones, cholesterol synthesizes a hormone called pregnenolone. This is done by cholesterol from the cytosol or lysosome being brought to the mitochondria and becoming fixed in the inner mitochondrial membrane. Once there, the cholesterol becomes pregnenolone through three reactions. The enzyme responsible for catalyzing all three reactions is CYP11A, a side chain cleavage enzyme. After being created, the pregnenolone enters the cytosol, where the cholesterol originated. Once in the cytosol, pregenolone synthesizes progesterone, using two reactions. These two reactions are both catalyzed by an enzyme called 3-beta-hydroxysteroid dehydrogenase/isomerase. The enzyme CYP21A2 then hydroxylates progesterone, which converts it to deoxycorticosterone. Deoxycorticosterone then undergoes three reactions catalyzed by CYP11B2 to become aldosterone. 17alpha-hydroxyprogesterone is created from pregnenolone by using 3-beta-hydroxysteroid dehydrogenase/isomerase. CYP21A2 then hydroxylates 17alpha-hydroxyprogesterone which results in the production of 11-deoxycortisol. CYP11B1 quickly converts 11-deoxycortisol to cortisol. Cortisol is an active steroid hormone, and its conversion to the inactive cortisone has been known to occur in various tissues, with increased conversion occurring in the liver. Pregnenolone is an important hormone as it is responsible for the beginning of the synthesis of many hormones not pictured in this pathway such as testosterone and estrogen. Cortisol receptors are found in almost every bodily cell, so this hormone affects a wide range of body functions. Some of these functions include metabolism regulation, inflammation reduction, regulating blood sugar levels and blood pressure, and helps with the formation of memories.

This pathway depicts the synthesis and breakdown of porphyrin. The porphyrin ring is the framework for the heme molecule, the pigment in hemoglobin and red blood cells. The first reaction in porphyrin ring biosynthesis takes place in the mitochondria and involves the condensation of glycine and succinyl-CoA by delta-aminolevulinic acid synthase (ALAS). Delta-aminolevulinic acid (ALA) is also called 5-aminolevulinic acid. Following its synthesis, ALA is transported into the cytosol, where ALA dehydratase (also called porphobilinogen synthase) dimerizes 2 molecules of ALA to produce porphobilinogen. The next step in the pathway involves the condensation of 4 molecules of porphobilinogen to produce hydroxymethylbilane (also known as HMB). The enzyme that catalyzes this condensation is known as porphobilinogen deaminase (PBG deaminase). This enzyme is also called hydroxymethylbilane synthase or uroporphyrinogen I synthase. Hydroxymethylbilane (HMB) has two main fates. Most frequently it is enzymatically converted into uroporphyrinogen III, the next intermediate on the path to heme. This step is mediated by two enzymes: uroporphyrinogen synthase and uroporphyrinogen III cosynthase. Hydroxymethylbilane can also be non-enzymatically cyclized to form uroporphyrinogen I. In the cytosol, the uroporphyrinogens (uroporphyrinogen III or uroporphyrinogen I) are decarboxylated by the enzyme uroporphyrinogen decarboxylase. These new products have methyl groups in place of the original acetate groups and are known as coproporphyrinogens. Coproporphyrinogen III is the most important intermediate in heme synthesis. Coproporphyrinogen III is transported back from the cytosol into the interior of the mitochondria, where two propionate residues are decarboxylated (via coproporphyrinogen-III oxidase), which results in vinyl substituents on the 2 pyrrole rings. The resulting product is called protoporphyrinogen IX. The protoporphyrinogen IX is then converted into protoporphyrin IX by another enzyme called protoporphyrinogen IX oxidase. The final reaction in heme synthesis also takes place within the mitochondria and involves the insertion of the iron atom into the ring system generating the molecule known heme b. The enzyme catalyzing this reaction is known as ferrochelatase. The largest repository of heme in the body is in red blood cells (RBCs). RBCs have a life span of about 120 days. When the RBCs have reached the end of their useful lifespan, the cells are engulfed by macrophages and their constituents recycled or disposed of. Heme is broken down when the heme ring is opened by the enzyme known as heme oxygenase, which is found in the endoplasmic reticulum of the macrophages. The oxidation process produces the linear tetrapyrrole biliverdin, ferric iron (Fe3+), and carbon monoxide (CO). The carbon monoxide (which is toxic) is eventually discharged through the lungs. In the next reaction, a second methylene group (located between rings III and IV of the porphyrin ring) is reduced by the enzyme known as biliverdin reductase, producing bilirubin. Bilirubin is significantly less extensively conjugated than biliverdin. This reduction causes a change in the colour of the molecule from blue-green (biliverdin) to yellow-red (bilirubin). In hepatocytes, bilirubin-UDP-glucuronyltransferase (bilirubin-UGT) adds two additional glucuronic acid molecules to bilirubin to produce the more water-soluble version of the molecule known as bilirubin diglucuronide. In most individuals, intestinal bilirubin is acted on by the gut bacteria to produce the final porphyrin products, urobilinogens and stercobilins. These are excreted in the feces. The stercobilins oxidize to form brownish pigments which lead to the characteristic brown colour found in normal feces. Some of the urobilinogen produced by the gut bacteria is reabsorbed and re-enters the circulation. These urobilinogens are converted into urobilins that are then excreted in the urine which cause the yellowish colour in urine.

Purine is a water soluble, organic compound. Purines, including purines that have been substituted, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable examples are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The main organ where purine nucleotides are created is the liver. This process starts as 5-phospho-α-ribosyl-1-pyrophosphate, or PRPP, and creates inosine 5’-monophosphate, or IMP. Following a series of reactions, PRPP uses compounds such as tetrahydrofolate derivatives, glycine and ATP, and IMP is produced as a result. Glutamine PRPP amidotransferase catalyzes PRPP into 5-phosphoribosylamine, or PRA. 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted tosuccinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP creates a fork in the road for the creation of purine, as it can either become GMP or AMP. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Purine nucleotides being catabolized creates uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. Nucleotide creation stemming from the purine bases and purine nucleosides happens in steps that are called the “salvage pathways”. The free purine bases phosphoribosylated and reconverted to their respective nucleotides.