Browsing Pathways

Plasmalogens are a class of phospholipids found in animals. Plasmalogens are thought to influence membrane dynamics and fatty acid levels, while also having roles in intracellular signalling and as antioxidants. Plasmalogens consist of a glycerol backbone with an vinyl-ether-linked alkyl chain at the sn-1 position, an ester-linked long-chain fatty acid at the sn-2 position, and a head group attached to the sn-3 position through a phosphodiester linkage. It is the vinyl-ether-linkage that separates plasmalogens from other phospholipids. Plasmalogen biosynthesis begins in the peroxisomes, where the integral membrane protein dihydroxyacetone phosphate acyltransferase (DHAPAT) catalyzes the esterification of the free hydroxyl group of dihydroxyacetone phosphate (DHAP) with a molecule any of long chain acyl CoA. Next, alkyl-DHAP synthase, a peroxisomal enzyme associated with DHAPAT, replaces the fatty acid on the DHAP with a long chain fatty alcohol. The third step of plasmalogen biosynthesis is catalyzed by the enzyme acyl/alkyl-DHAP reductase, which is found in the membrane of both the peroxisome and endoplasmic reticulum (ER). Acyl/alkyl-DHAP reductase uses NADPH as a cofactor to reduce the ketone of the 1-alkyl-DHAP using a classical hydride transfer mechanism. The remainder of plasmalogen synthesis occurs using enzymes in the ER. Lysophosphatidate acyltransferases (LPA-ATs) transfer the acyl component of a polyunsaturated acyl-CoA to the the 1-alkyl-DHAP, creating a 1-alkyl-2-acylglycerol 3-phosphate. The phosphate is then removed by lipid phosphate phosphohydrolase I (PAP-I), and the head group is attached by a choline/ethanolaminephosphotransferase. The majority of plasmalogens have either ethanolamine or choline as a headgroup, although a small amount of serine and inositol-linked ether-phospholipids can also be found. In the final step, the vinyl-ether linkage is created by plasmanylethanolamine desaturase, which catalyzes the formation of a double bond in the alkyl chain of the plasmalogen.

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.

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.

Alanine (L-Alanine) is an α-amino acid that is used for protein biosynthesis. Approximately 8% of human proteins have alanine in their structures. The reductive lamination of pyruvate is effected by alanine transaminase. L-Alanine can be converted to pyruvic acid by alanine aminotransferase 1 reversibly coupled with interconversion of oxoglutaric acid and L-glutamic acid. L-Alanine can also be produced by alanine-glyoxylate transaminase with coupled interconversion of glyoxylate and glycine. L-Alanine will be coupled with alanyl tRNA by alanyl-tRNA synthetase to perform protein biosynthesis. Alanine can also be used to provide energy under fasting conditions. There are two pathways that can facilitate this: (1) alanine is converted to pyruvate to synthesize glucose via the gluconeogenesis pathway in liver tissue or (2) alanine converted into pyruvate moves into the TCA cycle to be oxidized in other tissues.

Linoleic acid (LNA) is a polyunsaturated fatty acid (PUFA) precursor to the longer n−6 fatty acids commonly known as omega-6 fatty acids. Omega-6 fatty acids are characterized by a carbon-carbon double bond at the sixth carbon from the methyl group. Similarly, the PUFA alpha-linoleic acid (ALA) is the precursor to n-3 fatty acids known as omega-3 fatty acids which is characterized by a carbon-carbon double bond at the third carbon from the methyl group. Both LNA and ALA are essential dietary requirements for all mammals since they cannot be synthesized natively in the body. Both undergo a series of similar conversions to reach their final fatty acid form. LNA enters the cell and is catalyzed to gamma-linolenic acid (GLA) by acyl-CoA 6-desaturase (delta-6-desaturase/fatty acid desaturase 2). GLA is then converted to dihomo-gammalinolenic acid (DGLA) by elongation of very long chain fatty acids protein 5 (ELOVL5). DGLA is then converted to arachidonic acid (AA) by acyl-CoA (8-3)-desaturase (delta-5-desaturase/fatty acid desaturase 1). Arachidonic acid is then converted to a series of short lived metabolites called eicosanoids before finally reaching it's final fatty acid form.

Biotin is a vitamin that is an essential nutrient for humans. Biotin can be absorbed from consuming various foods such as: legumes, soybeans, tomatoes, romaine lettuce, eggs, cow's milk, oats and many more. Biotin acts as a cofactor for enzymes to catalyze carboxylation reactions involved in gluconeogenesis, amino acid catabolism and fatty acid metabolism. Biotin deficiency has been associated with many human diseases. These diseases may be caused by dysfunctional biotin metabolism due to enzyme deficiencies. Some research suggests biotin may play a role in transcription regulation or protein expression which may lead to biotin related diseases.

The semi-essential amino aid cysteine is tightly regulated in the body to ensure proper levels for metabolism but maintaining levels below toxic thresholds. Cysteine can be obtained from diet or synthesized from O-acetyl-L-serine. Cystine is the dimeric form of cysteine. Cysteine is a precursor for protein synthesis and an antioxidant. Impaired cysteine metabolism has been linked with neurodegenerative disorders.

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.

Fructose and mannose are monosaccharides that can be found in many foods. Fructose can join with glucose to form sucrose. Mannose can be converted to glucose. Both may be used as food sweeteners. Fructose is well absorbed, especially in the presence of glucose. Fructose causes less of an insulin response compared to glucose and thus may be a preferred sugar for diabetics. In contrast to fructose, humans do not metabolize mannose well with the majority of it being excreted unchanged. Mannose in the urine can be beneficial in treating urinary tract infections caused be E. coli. However, mannose can be detrimental to humans by causing diabetic complications.