Browsing pathways

Azithromycin, a semisynthetic antibiotic belonging to the macrolide subgroup of azalides, is used to treat STDs due to chlamydia and gonorrhea, community-acquired pneumonia, pelvic inflammatory disease, pediatric otitis media and pharyngitis, and Mycobacterium avium complex (MAC) in patients with advanced HIV disease. Similar in structure to erythromycin, azithromycin reaches higher intracellular concentrations than erythromycin, increasing its efficacy and duration of action. Azithromycin binds to the 50S subunit of the 70S bacterial ribosomes, and therefore inhibits RNA-dependent protein synthesis in bacterial cells.

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). Benazepril is an ACE inhibitor prodrug that is hydrolyzed by liver esterases to its active form, benazeprilat. Benazeprilat 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 benazepril. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of benazepril. Benazepril may be used to treat hypertension, congestive heart failure and chronic renal failure.

Bendroflumethiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, bendroflumethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Benzocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Benzocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore benzocaine preferentially inhibits neurons that are actively firing.

Fatty acid degradation in most organisms occurs primarily via the beta-oxidation cycle. In mammals, beta-oxidation occurs in both mitochondria and peroxisomes, whereas plants and most fungi harbor the beta-oxidation cycle only in the peroxisomes. In humans, fatty acid oxidation occurs in peroxisomes when the fatty acid chains are too long to be handled by the mitochondria. However, the oxidation ceases at octanyl CoA. It is believed that very long chain (greater than C-22) fatty acids undergo initial oxidation in peroxisomes which is followed by mitochondrial oxidation. One significant difference is that oxidation in peroxisomes is not coupled to ATP synthesis. Instead, the high-potential electrons are transferred to O2, which yields H2O2. The enzyme catalase, found exclusively in peroxisomes, converts the hydrogen peroxide into water and oxygen. Peroxisomal β-oxidation also requires enzymes specific to the peroxisome and to very long fatty acids. There are three key differences between the enzymes used for mitochondrial and peroxisomal β-oxidation: beta-oxidation in the peroxisome requires the use of a peroxisomal carnitine acyltransferase (instead of carnitine acyltransferase I and II used by the mitochondria) for transport of the activated acyl group into the peroxisome. The first oxidation step in the peroxisome is catalyzed by the enzyme acyl CoA oxidase. The beta-ketothiolase used in peroxisomal beta-oxidation has an altered substrate specificity, different from the mitochondrial beta-ketothiolase. In mitochondria, the beta-oxidation pathway includes four reactions that occur in repeating cycles with each fatty acid molecule. In each cycle, a fatty acid is progressively shortened by two carbons as it is oxidized and its energy captured by the reduced energy carriers NADH and FADH2. At the end of each cycle of four reactions, one acetyl-CoA two-carbon unit is released from the end of the fatty acid, which then goes through another round of beta-oxidation, continuing to oxidize and shorten even-chain fatty acids until they are entirely converted to acetyl-CoA. The acetyl-CoA generated in beta-oxidation enters the TCA cycle, where it is further oxidized to CO2, producing more reduced energy carriers, NADH and FADH2. These carriers produced in the TCA cycle, along with those produced directly in beta-oxidation, transfer their energy to the electron transport chain where they drive the creation of the proton gradient that supports mitochondrial ATP production. Another destination of acetyl-CoA is the production of ketone bodies by the liver that are transported to tissues like the heart and brain for energy.

Beta-ureidopropionase deficiency (Beta Alanine-Synthase Deficiency, UPB1, BUP1) is an autosomal recessive disease caused by mutations in the UPB1 gene which codes for beta-ureidopropionase. A deficiency in this enzyme results in accumulation of N-carbamyl-beta-amino acids. Symptoms include hypotonia, dystonic movements, scoliosis, microcephaly, and severe developmental delay.

Beta-alanine is formed by the proteolytic degradation of beta-alanine containing dipeptides: carnosine, anserine, balenine, and pantothenic acid (vitamin B5). These dipeptides are found in protein rich foods such as chicken, beef, pork and fish. Beta-alanine can also be formed in the liver from the catabolism of pyrimidine nucleotides which are broken down into uracil and dihydrouracil and then metabolized into beta-alanine and beta-aminoisobutyrate. Beta-alanine can also be formed via the action of aldehyde dehydrogenase on beta-aminoproionaldehyde which is generated from various aliphatic polyamines. Under normal conditions, beta-alanine is metabolized to aspartic acid through the action of glutamate decarboxylase. It can also be converted to malonate semialdehyde and thereby participate in propanoate metabolism. Beta-alanine is not a proteogenic amino acid.

Beta-Ketothiolase Deficiency (2-Methyl-3-Hydroxybutyric Acidemia; Mitochondrial Acetoacetyl-CoA Thiolase Deficiency; MAT Deficiency; T2 Deficiency; 3-KTD Deficiency; 3-Ketothiolase Deficiency) is an autosomal recessive disease caused by a mutation in the HADHB gene which codes for beta-ketathiolase. A deficiency in this enzyme results in accumulation of ammonia and ketone bodies in blood; and 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, 3-hydroxybutyric acid, tiglylglycine, and ketone bodies in urine. Symptoms include ketosis, seizures, organic acids in urine, and hyperammonemia. Treatment includes a low protein diet and L-carnitine.h3. h2.

Betaine (or trimethylglycine) is related to choline (trimethylaminoethanol), with the difference that the terminal carboxylic acid group of trimethylglycine has been reduced to a hydroxyl group in choline. Betaine is obtained by humans from foods, either as betaine or choline-containing compounds. The conversion of choline to betaine is a two-step enzymic process, which occurs in the liver and kidney. Choline is first oxidised to betaine aldehyde, a reaction catalysed by the mitochondrial choline oxidase (choline dehydrogenase). In a subsequent step, betaine aldehyde is further oxidised in the mitochondria or cytoplasm to betaine by betaine aldehyde dehydrogenase. Betaine functions very closely with choline, folic acid, vitamin B12 and S-adenosyl methionine SAMe. All of these compounds function as methyl donors. They carry and donate methyl functional groups to facilitate necessary chemical processes. The donation of methyl groups is important to proper liver function, cellular replication, and detoxification reactions. Betaine also plays a role in the manufacture of carnitine and serves to protect the kidneys from damage. Betaine also donates a methyl group to convert homocysteine to methionine in a reaction catalysed by BHMT (Betaine Homocysteine Methyltransferase). Methionine is then converted to SAMe by Methionine Adenosyl Transferase (MAT) using magnesium and adenosine triphosphate as co-factors. The product of demethylation of betaine is dimethylglycine.

Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm.