Pathways

Phytanic acid, a branched chain fatty acid, is an important component of fatty acid intake, occuring in meat, fish and dairy products. Due to its methylation, it cannot be a substrate for acyl-CoA dehydrogenase and cannot enter the mitochondrial beta oxidation pathway. Phytanic acid is instead activated to its CoA ester form by a CoA synthetase to phytanoyl-CoA, where it can begin the first cycle of alpha oxidation. Phytanoyl-CoA is a substrate for a specific alpha-hydroxylase (Phytanoyl-CoA hydroxylase), which adds a hydroxyl group to the α-carbon of phytanic acid, creating the 19-carbon homologue, pristanic acid. Pristanic acid then undergoes further metabolism through beta oxidation.

In man, phenylalanine is an essential amino acid which must be supplied in the dietary proteins. Once in the body, phenylalanine may follow any of three paths. It may be (1) incorporated into cellular proteins, (2) converted to phenylpyruvic acid, or (3) converted to tyrosine. Tyrosine is found in many high protein food products such as soy products, chicken, turkey, fish, peanuts, almonds, avocados, bananas, milk, cheese, yogurt, cottage cheese, lima beans, pumpkin seeds, and sesame seeds. Tyrosine can be converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Depicted in this pathway is the conversion of phenylalanine to phenylpyruvate (via amino acid oxidase or tyrosine amino transferase acting on phenylalanine), the incorporation of phenylalanine and/or tyrosine into polypeptides (via tyrosyl tRNA synthetase and phenylalyl tRNA synthetase) and the conversion of phenylalanine to tyrosine via phenylalanine hydroxylase. This reaction functions both as the first step in tyrosine/phenylalanine catabolism by which the body disposes of excess phenylalanine, and as a source of the amino acid tyrosine. The decomposition of L-tyrosine begins with an α-ketoglutarate dependent transamination through the tyrosine transaminase to para-hydroxyphenylpyruvate. The next oxidation step catalyzed by p-hydroxylphenylpyruvate-dioxygenase creates homogentisate. In order to split the aromatic ring of homogentisate, a further dioxygenase, homogentistate-oxygenase, is required to create maleylacetoacetate. Fumarylacetate is created by the action maleylacetoacetate-cis-trans-isomerase through rotation of the carboxyl group created from the hydroxyl group via oxidation. This cis-trans-isomerase contains glutathione as a coenzyme. Fumarylacetoacetate is finally split via fumarylacetoacetate-hydrolase into fumarate (also a metabolite of the citric acid cycle) and acetoacetate (3-ketobutyroate).

Histidine, an amino acid, plays an important role in the creation of proteins. It is unique as an amino acid as it is needed for nucleotide formation. The biosynthesis of histidine in adults begins with the condensation of ATP and PRPP (phosphoribosyl pyrophosphate) to form n-5-phosphoribosyl 1-pyrophosphate (phosphoribosyl-ATP). It is also worth noting that PRPP is the beginning compound for purine and pyrimidine creation. Subsequent histidine biosynthetic steps (from phosphoribosyl-ATP onwards) are likely to occur in the intestinal microflora. Elimination of the phosphate and the opening of the ring in phosphoribosyl-ATP forms phosphoribosyl-forminino-5-aminoimidazole-4-carboxamide ribonucleotide(phosphoribosyl-forminino-AICAR-phosphate). This is subsequently converted to 5-phosphoribulosyl-forminino-5-aminoimidazole-4-carboxamide ribonucleotide. Cleavage of this compound creates imidazole glycerol phosphate and AICAR (aminoimidazolecarboxamide ribonucleotide) with glutamine being involved as an amino group donor. AICAR is used again through the purine pathway while the imidazole glycerol phosphate is converted to imidazole acetal phosphate. Transamination yields histidinol phosphate which is then turned into histidinol, and then, finally, to histidine. L-histidine is catalyzed by histidine ammonia-lyase into urocanic acid. This acid is then converted to 4-imidazolone-5-propionic acid by urocanate hydratase. 4-imidazolone-5-propionic acid is then converted to formiminoglutamic acid, using the enzyme probable imidazolonepropionase. One last reaction occurs to allow for glutamate metabolism, as formiminoglutamic acid is converted to l-glutamic acid through the use of formimidoyltransferase-cyclodeaminase. Histidine is also a precursor for carnosine biosynthesis(via carnosine synthase), with beta-alanine being the rate limiting precursor. Anserine can be synthesized either from carnosine via carnosine N-methyltransferase or from 1-methylhistidine via carnosine synthase. Inversely, cytosolic non-specific dipeptidase catalyzes the synthesis of 1-methylhistidine from anserine. Histidine is found in meat, seeds, nuts and whole grains. It is a very important amino acid in keeping a pH of 7 in the body, as it acts as a shuttle for protons to maintain a balance of acids and bases in the blood and different tissues.

This pathway describes the production and subsequent metabolism of arachidonic acid, an omega-6 fatty acid. In resting cells arachidonic acid is present in the phospholipids (especially phosphatidylethanolamine and phosphatidylcholine) of membranes of the body’s cells, and is particularly abundant in the brain. Typically a receptor-dependent event, requiring a transducing G protein, initiates phospholipid hydrolysis and releases the fatty acid into the intracellular medium. Three enzymes mediate this deacylation reaction including phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD). Once released, free arachidonate has three possible fates: 1) reincorporation into phospholipids, 2) diffusion outside the cell, and 3) metabolism. Arachidonate metabolism is carried out by three distinct enzyme classes: cyclooxygenases, lipoxygenases, and cytochrome P450’s. Specifically, the enzymes cyclooxygenase and peroxidase lead to the synthesis of prostaglandin H2, which in turn is used to produce the prostaglandins, prostacyclin, and thromboxanes. The enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins. Some arachidonic acid is converted into midchain HETEs, omega-chain HETEs, dihydroxyeicosatrienoic acids (DHETs), and epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenase hydroxylase activity. Several products of these pathways act within neurons to modulate the activities of ion channels, protein kinases, ion pumps, and neurotransmitter uptake systems, affecting processes such as cellular proliferation, inflammation, and hemostasis. The newly formed eicosanoids may also exit the cell of origin and bind to G-protein-coupled receptors present on nearby neurons or glial cells.

This pathway describes the inactivation and catabolism of male (androgen) and female (estrogen) hormones. Many steroid hormones are transformed by sulfatases, dehydrogenases and glucuronide transferases to enhance their solubility and to facilitate their elimination. Inactivation means to convert an active compound into an inactive compound. Peripheral inactivation, which is inactivation caused by outside enzymes such as liver enzymes for example, is needed to maintain a steady-state level of plasma. This means that if either of these hormones are to be “chemical signals”, their half-life in the bloodstream has to be limited so that a variation in secretion rate can be emulated in the plasma. A large part of inactivation/catabolism occurs in the liver, although a little bit of catabolic activity does happen in the kidneys. Inactive androgens and estrogens are mostly eliminated in the urine. For this to happen, androgen and estrogen need to be converted to compounds that are less hydrophobic so that they are more soluble at higher concentrations. In this pathway, the conversion to a hydrophilic compound is an oxidation of a 17b-hydroxyl group. These hormones are needed for sexual development in both males and females.

The glucose-alanine cycle—also referred to in the literature as the Cahill cycle or the alanine cycle—involves muscle protein being degraded to provide more glucose to generate additional ATP for muscle contraction. It allows pyruvate and glutamate to be transported out of muscle tissue to the liver where gluconeogenesis takes place to supply the muscle tissue with more glucose as mentioned previously. To initiate the cycle, muscle and tissues that catabolize amino acids for fuel generate amino groups—most commonly in the form of glutamate—through the process of transamination. These amino groups are transferred via alanine aminotransferase to pyruvate (a product of glycolysis) to form alanine and alpha-ketoglutarate. Alanine subsequently moves through the circulatory system to the liver where the reaction previously catalyzed by alanine aminotransferase is reversed to produce pyruvate. This pyruvate is converted into glucose through the process of gluconeogenesis which subsequently is transported back to the muscle tissue. Meanwhile, glutamate dehydrogenase in the mitochondria catabolizes glutamate into ammonium. Ammonium moves on to form urea in the urea cycle.

Vitamin K describes a group of lipophilic, hydrophobic vitamins that exist naturally in two forms (and synthetically in three others): vitamin K1, which is found in plants, and vitamin K2, which is synthesized by bacteria. Vitamin K is an important dietary component because it is necessary as a cofacter in the activation of vitamin K dependent proteins. Metabolism of vitamin K occurs mainly in the liver. In the first step, vitamin K is reduced to its quinone form by a quinone reductase such as NAD(P)H dehydrogenase. Reduced vitamin K is the form required to convert vitamin K dependent protein precursors to their active states. It acts as a cofactor to the integral membrane enzyme vitamin K-dependent gamma-carboxylase (along with water and carbon dioxide as co-substrates), which carboxylates glutamyl residues to gamma-carboxy-glutamic acid residues on certain proteins, activating them. Each converted glutamyl residue produces a molecule of vitamin K epoxide, and certain proteins may have more than one residue requiring carboxylation. To complete the cycle, the vitamin K epoxide is returned to vitamin K via the vitamin K epoxide reductase enzyme, also an integral membrane protein. The vitamin K dependent proteins include a number of important coagulation factors, such as prothrombin. Thus, warfarin and other coumarin drugs act as anticoagulants by blocking vitamin K epoxide reductase.

This pathway describes the synthesis of the common phospholipids, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and cardiolipins. Phospholipid synthesis is mediated by two possible mechanisms: (1) A CDP-activated polar head group for attaches to the phosphate of phosphatidic acid or (2) A CDP-activated 1,2-diacylglycerol and an inactivated polar head group. The ER membrane is the primary site of phospholipid synthesis using precursors imported into the ER from the cytosol. To initiate the process, phosphatidic acid is generated by the linkage of two fatty acids associated with coenzyme A (CoA) carriers to glycerol-3-phosphate. This new molecule is inserted into the membrane where a phosphatase converts it into diacylglycerol or alternatively it is formed into phosphatidylinositol before the conversion. If the conversion into diacylglycerol occurs, the molecule has three possible fates depending on the type of polar head group attached: phosphatidylcholine, phosphatidylethanolamine, or phosphatidylserine. At their inception, a phospholipid is composed of a saturated fatty acid and unsaturated fatty acid on the C1 and C2 carbon of the glycerol backbone respectively. With the continuous remodelling of the phospholipid bilayer, this fatty acid distribution at these carbons changes. For example, acyl group remodelling changes the presence of acyl groups on the glycerol backbone (which were initially placed there by acyl transferases) and moves it further into the membrane as a consequence of the action of phospholipase A1 (PLA1) and phospholipase A2 (PLA2). Another modifying group that is usually added are alcohol-containing groups such as serine, ethanol amine, and choline which contain positively-charged nitrogen.

Lactose synthesis occurs only in the mammary glands, producing lactose (4-O-B-D-galactosylpyranosyl-a-D-glucopyranoside), the major sugar in milk. Lactose is created by joining two monosaccarides with a B1,4 glycosidic bond. Glucose is first converted to UDP-galactose via the enzyme galactose-1-phosphate uridylyltransferase. UDP-galactose is then transported into the Golgi by the UDP galactose translocator, an antiporter which uses facilitated transport to move UDP galactose into the Golgi and exports UMP. Once inside the Golgi, the UDP galactose and glucose (which moves into the golgi via the GLUT-1 transporter) become substrates for the lactose synthase enzyme complex, comprised of the enzymatic subunit, galactosyltransferase with its regulatory subunit, Alpha-lactalbumin. Lactose synthase creates lactose through bonding galactose from UDP to glucose through a glycosidic bond. Although GT is found in many tissues in the body, Alpha-lactalbumin is only found on the inner surface of the Golgi in the mammary glands, limiting lactose production to the mammaries.

The steroid biosynthesis (or cholesterol biosynthesis) pathway is an anabolic metabolic pathway that produces steroids from simple precursors. It starts with the mevalonate pathway, where acetyl-CoA and acetoacetyl-CoA are the first two building blocks. These compounds are joined together via the enzyme hydroxy-3-methylgutaryl (HMG)-CoA synthase to produce the compound known as hydroxy-3-methylgutaryl-CoA (HMG-CoA). This compound is then reduced to mevalonic acid via the enzyme HMG-CoA reductase. It is important to note that HMG-CoA reductase is the protein target of many cholesterol-lowering drugs called statins (PMID: 12602122). The resulting mevalonic acid (or mevalonate) is then phosphorylated by the enzyme known as mevalonate kinase to form mevalonate-5-phosphate, which is then phosphorylated again by phosphomevalonate kinase to form mevolonate-5-pyrophsophate. This pyrophosphorylated compound is subsequently decarboxylated via the enzyme mevolonate-5-pyrophsophate decarboxylase to form isopentylpyrophosphate (IPP). IPP can also be isomerized (via isopentenyl-PP-isomerase) to form dimethylallylpyrophosphate (DMAPP). IPP and DMAPP can both donate isoprene units, which can then be joined together to make farnesyl and geranylgeranyl intermediates. Specifically, three molecules of IPP condense to form farnesyl pyrophosphate through the action of the enzyme known as geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form a molecule known as squalene by the action of the enzyme known as squalene synthase in the cell’s endoplasmic reticulum. The enzyme oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanosterol is a tetracyclic triterpenoid, and serves as the framework from which all steroids are derived. 14-Demethylation of lanosterol by a cytochrome P450 enzyme known as CYP51 eventually yields cholesterol. Cholesterol is the central steroid in human biology. It can be obtained from animal fats consumed in the diet or synthesized de novo (as described above). Cholesterol is an essential constituent of lipid bilayer membranes (where it forms cholesterol esters) and is the starting point for the biosynthesis of steroid hormones, bile acids and bile salts, and vitamin D. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (via glucocorticoids such as cortisol), salt balance (mineralocorticoids such as aldosterone), and sexual development and function (via androgens such as testosterone and estrogens such as estradiol). Bile acids and bile salts (such as taurocholate) are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Cholesterol is the main constituent of atheromas. These are the fatty lumps found in the walls of arteries that occur in atherosclerosis and, when ruptured, can cause heart attacks.