Browsing pathways

Smith-Lemli-Opitz Syndrome (SLOS; SLO Syndrome; RSH; Rutledge Lethal Multiple Congenital Anomaly, Syndrome; Polydactyly, Sex Reversal, Renal Hypoplasia, and Unilobar Lung; Lethal Acrodysgenital Syndrome) is an autosomal recessive disorder of steroid biosynthesis caused by a mutation in the DHCR7 gene, which codes for the enzyme sterol delta-7-reducatase. This enzyme catalyzes the production of cholesterol by reduction of C7-C8 double bond of 7-dehydrocholesterol (7-DHC). SLOS is characterized by accumulation of 7-dehydrocholesterol and 8-dehydrocholesterol, and a decrease of cholesterol in plasma; and 3-methylglutaconic acid in urine. All patients with SLOS have mental retardation, and symptoms include ambiguous genitalia, hypotonia, microcephaly, syndactyly, limb abnormalities and deformities and polydactyly.

Spectinomycin is an aminocyclitol antibiotic produced by a soil microorganism called Streptomyces spectabilis. Spectinomycin reversibly interferes with the interaction between mRNA and the bacterial 30S ribosomal subunit. It is structurally similar to aminoglycosides, but does not cause misreading of mRNA. In vitro studies have shown that spectinomycin has a bacteriostatic effect against most strains of Neisseria gonorrhoeae (minimum inhibitory concentration <7.5 to 20 mcg/mL). Footprint studies indicate that spectinomycin exerts regional effects on ribosomal structure. Spectinomycin may be used in the treatment of penicillin-resistant Neisseria gonorrhoeae.

The Spermidine and Spermine Biosynthesis pathway highlights the creation of these cruicial polyamines. Spermidine and spermine are produced in many tissues, as they are involved in the regulation of genetic processes from DNA synthesis to cell migration, proliferation, differentiation and apoptosis. These positiviely charged amines interact with negatively charged phosphates in nucleic acids to exert their regulatory effects on cellular processes. Spermidine originates from the action of spermidine synthase, which converts the methionine derivative S-adenosylmethionine and the ornithine derivative putrescine into spermidine 5'-methylthioadenosine. Spermidine is subsequently processed into spermine by spermine synthase in the presence of the aminopropyl donor, S-adenosylmethioninamine.

The sphingolipids, like the phospholipids, are composed of a polar head group and two nonpolar tails. The core of sphingolipids is the long-chain amino alcohol, sphingosine. Amino acylation, with a long chain fatty acid, at carbon 2 of sphingosine yields a ceramide. The sphingolipids include the sphingomyelins and glycosphingolipids (the cerebrosides, sulfatides, globosides and gangliosides). Sphingomyelins are the only sphingolipid that are phospholipids. Sphingolipids are a component of all membranes but are particularly abundant in the myelin sheath. De novo sphingolipid synthesis begins with formation of 3-keto-dihydrosphingosine by serine palmitoyltransferase. The preferred substrates for this reaction are palmitoyl-CoA and serine. Next, 3-keto-dihydrosphingosine is reduced to form dihydrosphingosine. Dihydrosphingosine is acylated by a (dihydro)-ceramide synthase to form dihydroceramide. This is desaturated to form ceramide. Ceramide may subsequently have several fates. It may be phosphorylated by ceramide kinase to form ceramide-1-phosphate. Alternatively, it may be glycosylated by glucosylceramide synthase or galactosylceramide synthase. Additionally, it can be converted to sphingomyelin by the addition of a phosphorylcholine headgroup by sphingomyelin synthase. Diacylglycerol is also generated via this process. Finally, ceramide may be broken down by a ceramidase to form sphingosine. Sphingosine may be phosphorylated to form sphingosine-1-phosphate, which may, in turn, be dephosphorylated to regerenate sphingosine. Sphingolipid catabolism allows the reversion of these metabolites to ceramide. The complex glycosphingolipids are hydrolyzed to glucosylceramide and galactosylceramide. These lipids are then hydrolyzed by beta-glucosidases and beta-galactosidases to regenerate ceramide. Similarly, sphingomyelin may be broken down by sphingomyelinase to create ceramide. The only route by which sphingolipids are converted to non-sphingolipids is through sphingosine-1-phosphate lyase. This forms ethanolamine phosphate and hexadecenal.

The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown). Spirapril is an ACE inhibitor prodrug that is hydrolyzed by liver esterases to its active form, spiraprilat. Spiraprilat competes with angiotensin I for binding to ACE and effectively blocks the conversion of angiotensin I to angiotensin II. The resulting decreased concentration of angiotensin II confers blood pressure lowering effects to spirapril. Increased bradykinin levels resulting from decreased bradykinin inactivation also contribute to the effects of spirapril. Spirapril may be used to treat hypertension and congestive heart failure.

Spironolactone is a potassium-sparing diuretic. It acts by competing with aldosterone for its receptor inside the principal cells of the late distal tubule and collecting tubule. Aldosterone increases sodium reabsorption and potassium excretion by up-regulating the expression of basolateral sodium-potassium ATPases as well as luminal (apical) sodium and potassium channels. Sodium in the nephron lumen enters the principal cells through the luminal sodium channels, where it is then actively pumped out into the interstitium by sodium-potassium ATPases. This causes the interstitium to become hyperosmotic and establishes an osmotic gradient, facilitating water reabsorption through aquaporin channels. On the other hand, potassium is actively pumped from the interstitium into the principle cell. It then diffuses from inside the cell into the nephron lumen via potassium channel, driven by an electrochemical gradient established by sodium leaving the lumen. Potassium entering the nephron lumen is subsequently excreted in the urine. Spironolactone inhibits sodium and water reabsorption as well as potassium excretion by blocking the actions of aldosterone as described above.

Carbohydrates are a major component of the human diet, and include starch (amylose and amylopectin) and disaccharides such as sucrose, lactose, maltose and, in small amounts, trehalose. The digestion of starch begins with the action of amylase enzymes secreted in the saliva and small intestine, which convert it to maltotriose, maltose, limit dextrins, and some glucose. Digestion of the limit dextrins and disaccharides, both dietary and starch-derived, to monosaccharides - glucose, galactose, and fructose - is accomplished by enzymes located on the luminal surfaces of enterocytes lining the microvilli of the small intestine. Once released from starch or once ingested, sucrose can be degraded into beta-D-fructose and alpha-D-glucose via lysosomal alpha-glucosidase or sucrose-isomaltase. Beta-D-fructose can be converted to beta-D-fructose-6-phosphate by glucokinase and then to alpha-D-glucose-6-phosphate by the action of glucose phosphate isomerase. Phosphoglucomutase 1 can then act on alpha-D-glucose-6-phosphate (G6P) to generate alpha-D-glucose-1-phosphate. Alpha-D-glucose-1-phosphate (G6P) has several possible fates. It can enter into gluconeogenesis, glycolysis or the nucleotide sugar metabolism pathway. UDP-glucose pyrophosphorylase 2 can convert alpha-D-glucose-1-phosphate into UDP-glucose, which can then be converted to UDP-xylose or UDP-glucuronate and, eventually to glucuronate. UDP-glucose can also serve as a precursor to the synthesis of glycogen via glycogen synthase. More specifically, glycogen is synthesized from monomers of UDP-glucose by the enzyme glycogen synthase, which progressively lengthens the glycogen chain with (α1→4) bonded glucose. As glycogen synthase can only lengthen an existing chain, the protein glycogenin is needed to initiate the synthesis of glycogen. The glycogen-branching enzyme, amylo (α1→4) to (α1→6) transglycosylase, catalyzes the transfer of a terminal fragment of 6-7 glucose residues from a nonreducing end to the C-6 hydroxyl group of a glucose residue deeper into the interior of the glycogen molecule. The branching enzyme can only act upon a branch having at least 11 residues, and the enzyme may transfer to the same glucose chain or adjacent glucose chains. Another enzyme known as starch phosphorylase or glycogen phosphorylase can also convert starch into glycogen. Glycogen functions as the secondary short term energy storage in animal cells. It is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach. Glycogen is the analogue of starch, a less branched glucose polymer in plants, and is commonly referred to as animal starch, having a similar structure to amylopectin. Glycogen is found in the form of granules in the cytosol in many cell types, and plays an important role in the glucose cycle. Glycogen is cleaved from the nonreducing ends of the chain by the enzyme glycogen phosphorylase to produce monomers of glucose-1-phosphate that is then converted to glucose 6-phosphate (G6P). G6P can continue on the glycolysis pathway and be used as fuel or G6P can enter the pentose phosphate pathway via the enzyme glucose-6-phosphate dehydrogenase to produce NADPH and 5-carbon sugars or, in the liver and kidney, G6P can be dephosphorylated back to glucose by the enzyme glucose 6-phosphatase. This is the final step in the gluconeogenesis pathway.

Steroid biosynthesis (Cholesterol Biosynthesis) is an anabolic metabolic pathway that produces steroids from simple precursors. It starts in the mevalonate pathway, (HMG-CoA reductase pathway, mevalonate-dependent (MAD) route, isoprenoid pathway), in humans, with Acetyl-CoA and Acetoacetyl-CoA as the first two building blocks. These are joined together via HMG-CoA synthase to produce hydroxy-3-methylgutaryl-CoA (HMG-CoA), which is then reduced to mevalonic acid via the enzyme HMG-CoA reductase. HMG-CoA reductase is the protein target of many cholesterol lowering drugs called statins. The mevaolonic acid is then phosphorylated by mevalonate kinase and subsequently decarboxylated to form isopentylpyrophosphate (IPP). IPP can also be isomerized to form dimethylallylpyrophosphate (DMAPP). Isopentenyl pyrophosphate and dimethylallylpyrophosphate donate isoprene units, which can be joined together to make farnesyl and geranylgeranyl intermediates. Specifically, three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum. Oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanosterol is a tetracyclic triterpenoid, which is the compound from which all steroids are derived. 14-Demethylation of lanosterol by 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 and is the starting point for the biosyntheses of bile acids and salts, steroid hormones, and vitamin D. Bile acids and salts, e.g., taurocholate, are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (glucocorticoids such as cortisol), salt balance (mineralocorticoids such as aldosterone), and sexual development and function (androgens and estrogens such as estradiol).

Steroidogenesis is the process wherein desired forms of steroids are generated by transformation of other steroids. Products of steroidogenesis include androgens, testosterone, estrogens and progesterone, corticoids, cortisol and aldosterone. The first step in the synthesis of all steroid hormones is the synthesis of pregnenolone from cholesterol. In this process, cholesterol mobilized from cytosolic lipid droplets or from lysosomes is transported to mitochondria and becomes localized to the inner mitochondrial membrane. In the inner mitochondrial membrane, cholesterol is converted to pregnenolone in a sequence of three reactions, all catalyzed by CYP11A (side chain cleavage enzyme). Finally, pregnenolone re-enters the cytosol. Aldosterone, the major human mineralocorticoid, is synthesized in the zona glomerulosa of the adrenal cortex from pregnenolone. Pregnenolone is converted to progesterone in two reactions, both catalyzed by 3-beta-hydroxysteroid dehydrogenase/isomerase. Progesterone is hydroxylated by CYP21A2 to form deoxycorticosterone, which in turn is converted to aldosterone in a three-reaction sequence catalyzed by CYP11B2. Cortisol, the major human glucocorticoid, is synthesized in the zona fasciculata of the adrenal cortex from pregnenolone. Pregnenolone is converted to 17alpha-hydoxyprogesterone in two reactions, both catalyzed by 3-beta-hydroxysteroid dehydrogenase/isomerase. 17Alpha-hydroxyprogesterone is hydroxylated by CYP21A2 to form 11-deoxycortisol, which in turn is converted to cortisol by CYP11B1. The conversion of the active steroid hormone, cortisol, to inactive cortisone occurs in many tissues, notably the liver. Testosterone biosynthesis begins with pregnenolone. Subsequent steps require several enzymes including, 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase/C17-20-lyase and 17β-hydroxysteroid dehydrogenase type 3. Specifically, pregnenolone is converted to 17-hydroxypregnenolone and dehydroepiandrosterone by CYP17 (17α-hydroxylase). Dehydroepiandrosterone is then converted to androstenedione by 3β-hydroxysteroid dehydrogenase. Androstenedione can have two fates, it can either be converted to estrone via CYP19 (aromatase/estrogen synthase) or it can be converted to testosterone via 17β-hydroxysteroid dehydrogenase. Free testosterone is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha reductase. Testosterone may also be converted to estradiol by the action of CYP19 (aromatase/estrogen synthase).

Streptokinase cleaves the Arg/Val bond in plasminogen to form the proteolytic enzyme plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction.