Pathways

Ethanol metabolism in humans occurs mainly in the liver, though degradation has also been shown in gastric, pancreatic, and lung tissue. Ethanol degradation occurs via four pathways, three of which are oxidative pathways and are depicted here. The fourth is a nonoxidative pathway which is less well studied but known to produce fatty acid ethyl esters. Each of the three oxidative pathways is differentiated by the mechanism utilized to oxidize ethanol to acetaldehyde in the first step. In the alcohol dehydrogenase mediated ethanol degradation pathway (I), cytoplasmic alcohol dehydrogenase produces the acetaldehyde from the ethanol. In the MEOS mediated ethanol degradation pathway (II), the ethanol enters the endoplasmic reticulum, where the Microsomal Ethanol Oxidising System (MEOS), also know as also known as cytochrome P-450 2E1, does the oxidizing and returns the acetaldehyde to the cytoplasm. In the catalase mediated ethanol degradation pathway (III), the oxidation occurs in the peroxisome via peroxisomal catalase, with the resulting acetaldehyde being released to the cytoplasm. In each of the three oxidative pathways the cytosolic acetaldehyde then enters the mitochondrial compartment, where it is converted to acetate by mitochondrial aldehyde dehydrogenase. The acetate leaves the mitochondria and moves to extra-hepatic tissues for further metabolism. In extra-hepatic cells the acetate is converted to acetyl-CoA via either cytoplasmic or mitochondrial acetyl-CoA synthetase. The alcohol dehydrogenase mediated ethanol degradation pathway (I) is the predominant mechanism of catabolism under conditions of acute alcohol consumption. However, under conditions of chronic ethanol consumption the MEOS mediated ethanol degradation pathway (II) and nonoxidative pathway are induced to assist with ethanol degradation.

Cells typically contain large amounts of C18 and C20 fatty acids. Longer chain fatty acids are found in certain specialized tissues (myelin contains high amounts of C22 and C24 components). Even longer chain fatty acids are derived from either dietary sources or from elongation of C16-CoA or C18-CoA formed by the cytoplasmic fatty acid synthetase system. All of the fatty acids needed by the body can be synthesized from palmitate (C16:0) except the essential, polyunsaturated fatty acids such as linoleate and linolenate. To create longer, shorter, oxidized, reduced fatty acids, palmitic acid is subjected to enzymatic reactions by reductases, hydroxylases, elongases and mixed function oxidases. There are 3 major processes that modify palmitic acid: elongation, desaturation and hydroxylation. Elongation of fatty acids may occur at endoplasmic reticulum where fatty acid molecules of length up to C24 may be produced. Mitochondrial elongation may result in fatty acids up to C16 in length. Fatty acid elongation in mitochondria is essentially the reverse of beta-oxidation for fatty acid oxidation. In particular, both pathways make use of acetyl-CoA acyltransferase, 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase. The final step of fatty acid elongation uses enoyl-CoA reductase (not part of the beta-oxidation pathway). The elongation takes place in the mitochondrial matrix. In liver and kidney fatty acid elongation operates best in the presence of both NADH and NADPH, whereas in heart and skeletal muscle, only NADH is required. The mitochondrial pathway is important for elongating fatty acids containing 14 or fewer carbon atoms. Short chain fatty acids (SCFA) are fatty acids with aliphatic tails of less than six carbons. Medium chain fatty acids (MCFA) are fatty acids with aliphatic tails of 6Š—–12 carbons. Long chain fatty acids (LCFA) are fatty acids with aliphatic tails longer than 12 carbons. Very Long chain fatty acids (VLCFA) are fatty acids with aliphatic tails longer than 22 carbons.

Fatty acids constitute a large energy source for the body. The cellular membrane is also made up of fatty acids. During starvation times, fatty acids can provide energy to humans for numerous days. Fatty acid metabolism is also known as beta-oxidation. During metabolism, acetyl CoA is produced that can then enter the citric acid cycle. When ATP is needed, ATP may be generated by increasing fatty acid metabolism. Fatty acid metabolism is essentially the reverse reaction of fatty acid synthesis.

Folate, or folic acid, is a very important B-vitamin involved in cell creation and preservation, as well as the protection of DNA from mutations that can cause cancer. It is commonly found in leafy green vegetables, but is also present in many other foods such as fruit, dairy products, eggs and meat. Folate is imperative during pregnancy as a deficiency will cause neural tube defects in the offspring. Many countries around the world now fortify foods with folic acid to prevent such defects. This pathway begins in the extracellular space, where folic acid is transported into the cell through a proton-coupled folate transporter. From there, dihydrofolate reductase converts folic acid into dihydrofolic acid. Dihydrofolic acid is then created into tetrahydrofolic acid through dihydrofolate reductase. Tetrahydrofolic acid then sparks the beginning of many reactions and subpathways including purine metabolism and histidine metabolism. There are two reactions that tetrahydrofolic acid undergoes, the first being the catalyzation into tetrahydrofolyl-[glu](2) through the enzyme folylpolyglutamate synthase in the mitochondria. Then, tetrahydrofolyl-[glu](2) becomes tetrahydrofolyl-[glu](n) through folylpolyglutamate synthase. The cycle ends with tetrahydrofolyl-[glu](n) reverting to tetrahydrofolyl-[glu](2) in the lysosome through the enzyme gamma-glutamyl hydrolase. The second reaction that begins with tetrahydrofolic acid sees tetrahydrofolic acid turned into 10-formyltetrahydrofolate through c-1-tetrahydrofolate synthase. This loop is completed by cytosolic 10-formyltetrahydrofolate dehydrogenase reverting 10-formyltetrahydrofolate back to tetrahydrofolic acid. Folate is not stored in the body for very long, as it is a water soluble vitamin and is excreted through urine, so it is important to ingest it continually, as your body’s level of folate will decline after a few weeks if the vitamin is avoided.

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.

The glycerol phosphate shuttle also known as the glycerophosphate shuttle. It shuttles electrons to mitochondrial carriers in the oxidative phosphorylation pathway from cytosolic NADH. This shuttle relies on mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH). This is also a common process for the cell to regenerate cytosolic NAD+ for other processes.

Homocysteine is an amino acid and homologue of cysteine that appears in the body as a result of the degradation of methionine. In mammals, homocysteine is used to biosynthesize cysteine via the following pathway. First the enzyme cystathionine beta-synthetase irreversibly condenses homocysteine with L-serine, forming L-cystathionine. The L-cystathionine is then cleaved by cystathionine gamma-lyase, producing 2-oxobutanoate, L-cysteine, and ammonia. The 2-oxobutanoate is further broken down via the 2-oxobutanoate degradation pathway, producing citric acid cycle intermediates, while the L-cysteine goes to the cysteine metabolism pathway. The homocysteine degradation pathway composes a part of the larger methionine metabolism pathway.

Ketone bodies are consisted of acetone, beta-hydroxybutyrate and acetoacetate. In liver cells' mitochondria, acetyl-CoA can synthesize acetoacetate and beta-hydroxybutyrate; and spontaneous decarboxylation of acetoacetate will form acetone. Metabolism of ketone body (also known as ketogenesis) contains several reactions. Acetoacetic acid (acetoacetate) will be catalyzed to form acetoacetyl-CoA irreversibly by 3-oxoacid CoA-transferase 1 that also coupled with interconversion of succinyl-CoA and succinic acid. Acetoacetic acid can also be catalyzed by mitochondrial D-beta-hydroxybutyrate dehydrogenase to form (R)-3-Hydroxybutyric acid with NADH. Ketogenesis occurs mostly during fasting and starvation. Stored fatty acids will be broken down and mobilized to produce large amount of acetyl-CoA for ketogenesis in liver, which can reduce the demand of glucose for other tissues. Acetone cannot be converted back to acetyl-CoA; therefore, they are either breathed out through the lungs or excreted in urine.

The degradation of L-lysine happens in liver and it is consisted of seven reactions. L-Lysine is imported into liver through low affinity cationic amino acid transporter 2 (cationic amino acid transporter 2/SLC7A2). Afterwards, L-lysine is imported into mitochondria via mitochondrial ornithine transporter 2. L-Lysine can also be obtained from biotin metabolism. L-Lysine and oxoglutaric acid will be combined to form saccharopine by facilitation of mitochondrial alpha-aminoadipic semialdehyde synthase, and then, mitochondrial alpha-aminoadipic semialdehyde synthase will further breaks saccharopine down to allysine and glutamic acid. Allysine will be degraded to form aminoadipic acid through alpha-aminoadipic semialdehyde dehydrogenase. Oxoadipic acid is formed from catalyzation of mitochondrial kynurenine/alpha-aminoadipate aminotransferase on aminoadipic acid. Oxoadipic acid will be further catalyzed to form glutaryl-CoA, and glutaryl-CoA converts to crotonoyl-CoA, and crotonoyl-CoA transformed to 3-hydroxybutyryl-CoA. 3-Hydroxybutyryl-CoA will form Acetyl-CoA as the final product through the intermediate compound: acetoacetyl-CoA. Acetyl-CoA will undergo citric acid cycle metabolism. Carnitine is another key byproduct of lysine metabolism (not shown in this pathway).

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.