By L. Onatas. Jewish Theological Seminary. 2018.
Pyridoxal phosphate is synthesized from the vitamin pyridoxine kamagra effervescent 100mg online erectile dysfunction causes prescription drugs, which is also called vitamin B6 (Fig safe 100mg kamagra effervescent erectile dysfunction statistics singapore. The reactive aldehyde group usually func- tions in enzyme-catalyzed reactions by forming a covalent bond with the amino groups on amino acids. The positively charged ring nitrogen withdraws elec- trons from a bond in the bound amino acid, resulting in cleavage of that bond. The enzyme participates by removing protons from the substrate and by keep- ing the amino acid and the pyridoxal group in a single plane to facilitate shut- tling of electrons. CoASH O Reactive group Forms thioesters with acyl groups ( )CR O SH O C CH2 – OH O P O CH2 – O + NH CH3 N C O H CH2 Pyridoxal phosphate (PLP) CH2 Phospho– Fig. The functional group of pyridoxal phos- C O phate is a reactive aldehyde (shown in blue) H C OH that forms a covalent intermediate with amino H3C C CH3 groups of amino acids (a Schiff base). The pos- NH2 CH itively charged pyridine ring is a strong elec- 2 N N tron-withdrawing group that can pull electrons O O– H into it (electrophilic catalysis). Biotin Reactive group O CO2 HN NH H Lysine HN N S CH O C Biotin O The biotin–lysine (biocytin) complex Fig. Coenzyme A (CoA or CoASH) and phosphopantetheine are synthesized from the vitamin pantothenate (pantothenic acid). The active sulfhydryl group, shown in blue, binds to acyl groups (e. Biotin activates and transfers CO2 to compounds in car- boxylation reactions. Biotin is covalently attached to a lysine residue in the carboxylase enzyme. In general, coenzymes are nonpro- tein organic cofactors that partici- These coenzymes illustrate three features all activation-transfer coenzymes have pate in reactions. They may be in common: (1) a specific chemical group involved in binding to the enzyme, (2) a covalently bound to enzymes (like biotin), separate and different functional or reactive group that participates directly in the dissociate during deficiency (thiamine- catalysis of one type of reaction by forming a covalent bond with the substrate, and pyrophosphate), or freely dissociate at the (3) dependence on the enzyme for additional specificity of substrate and additional end of the reaction (CoASH). A prosthetic group, such as the heme in hemoglobin, usually does not A large number of coenzymes are involved in oxidation-reduction reactions dissociate from a protein until the protein is catalyzed by enzymes categorized as oxidoreductases. As a result, the oxi- can transfer electrons together with hydrogen and have unique roles in the genera- dized carbon has fewer H atoms or tion of ATP from the oxidation of fuels. Other oxidation-reduction coenzymes work gains an O atom. The reduction of a com- with metals to transfer single electrons to oxygen. Vitamin E and vitamin C (ascor- pound is the gain of electrons, which shows bic acid) are oxidation-reduction coenzymes that can act as antioxidants and protect in its structure as the gain of H, or loss of O. The different functions of oxidation-reduction In the oxidation of lactate to pyruvate (see Fig. The carbon atom with the coenzyme has a unique functional group that accepts and donates electrons and is keto group is now at a higher oxidation state specific for the form of electrons it transfers (e. A different portion of the coenzyme binds the enzyme. Like activation- between carbon and oxygen are counted as transfer coenzymes, oxidation-reduction coenzymes are not good catalysts without belonging to oxygen, whereas the two elec- participation from amino acid side chains on the enzyme. The coenzyme nicoti- The catalysis of oxidation-reduction reac- namide adenine dinucleotide (NAD ) is synthesized from the vitamin niacin (which tions is carried out by a class of enzymes called oxidoreductases. A subclass of oxidore- forms the nicotinamide ring), and from ATP (which contributes an AMP). The ADP ductases is given the common name dehy- portion of the molecule binds tightly to the enzyme and causes conformational drogenases (such as lactate dehydrogenase), because they transfer hydrogen (hydrogen atoms or hydride atoms) from the substrate to Lactate Pyruvate an electron-accepting coenzyme, such as NAD. COO– COO– Dissociates as H+ H O C H C + + CH3 CH3 O H O C NH2 C NH2 + O N N – O Nicotinamide R O P 2 H H H H HO OH O NH2 C N N C CH AMP provides additional HC C N binding interactions N – which induce O P O 2 conformational changes NAD+ in the enzyme O H H R = H H H + O HO OR NADP R = P O– O– Fig. NAD - dependent dehydrogenases catalyze the transfer of a hydride ion (H:) from a carbon to NAD in oxidation reactions such as the oxidation of alcohols to ketones or aldehydes to acids. The positively charged pyridine ring nitrogen of NAD increases the electrophilicity of the car- bon opposite it in the ring. This carbon then accepts the negatively charged hydride ion. The proton from the alcohol group is released into water. NADP functions by the same mecha- nism, but it is usually involved in pathways of reductive synthesis.
Regulation of RNA Polymerase Binding by Repressors In bacteria buy kamagra effervescent 100 mg with amex erectile dysfunction drugs without side effects, the principle means of regulating gene transcription is through repres- sors kamagra effervescent 100 mg low price erectile dysfunction how common, which are regulatory proteins that prevent the binding of RNA polymerase to the promoter and, thus, act on initiation of transcription (Fig. The structural genes of an operon are transcribed as one long poly- cistronic mRNA. During translation, different start (AUG) and stop (shown in blue) codons lead to a number of distinct proteins being produced from this single mRNA. CHAPTER 16 / REGULATION OF GENE EXPRESSION 277 regulatory mechanisms such as repressors that work through inhibition of gene tran- Repressors scription are referred to as negative control, and mechanisms that work through Regulatory gene stimulation of gene transcription are called positive control. DNA The repressor is encoded by a regulatory gene (see Fig. Although this gene is considered part of the operon, it is not always located near the remainder mRNA of the operon. Its product, the repressor protein, diffuses to the promoter and binds to a region of the operon called the operator. The operator is located within the promoter or near its 3 -end, just upstream from the transcription startpoint. When a repressor is bound to the operator, the operon is not transcribed because Repressor the repressor blocks the binding of RNA polymerase to the promoter. Two regu- latory mechanisms work through controlling repressors: induction (an inducer Promoter Structural genes inactivates the repressor), and repression (a co-repressor is required to activate Operator A B C the repressor). INDUCERS No transcription occurs Induction involves a small molecule, known as an inducer, which stimulates expres- No proteins are produced sion of the operon by binding to the repressor and changing its conformation so that Fig. Regulation of operons by repres- it can no longer bind to the operator (Fig. When the repressor protein is bound to a metabolite of the nutrient. In the presence of the inducer, RNA polymerase can the operator, RNA polymerase cannot bind, therefore bind to the promoter and transcribe the operon. The key to this mechanism and transcription therefore does not occur. Consider, for example, induction of the lac operon of E. The enzymes for metabolizing glucose by glycolysis are produced constitu- Inducers tively; that is, they are constantly being made. If the milk sugar lactose is available, Promoter Structural genes the cells adapt and begin to produce the three additional enzymes required for lac- Operator A B C tose metabolism, which are encoded by the lac operon. A metabolite of lactose (allolactose) serves as an inducer, binding to the repressor and inactivating it. Because the inactive repressor no longer binds to the operator, RNA polymerase can Repressor No transcription occurs bind to the promoter and transcribe the structural genes of the lac operon, produc- (active) No proteins are produced ing a polycistronic mRNA that encodes for the three additional proteins. However, Inducer the presence of glucose can prevent activation of the lac operon (see “Stimulation of RNA polymerase binding,” below). COREPRESSORS Repressor (inactive) In a regulatory model called repression, the repressor is inactive until a small mol- ecule called a corepressor (a nutrient or its metabolite) binds to the repressor, acti- RNA polymerase vating it (Fig. The repressor–corepressor complex then binds to the operator, preventing binding of RNA polymerase and gene transcription. Consider, for exam- ple, the trp operon, which encodes the five enzymes required for the synthesis of the Transcription amino acid tryptophan. Tryptophan is a corepressor that binds to the inac- Polycistronic tive repressor, causing it to change conformation and bind to the operator, thereby mRNA inhibiting transcription of the operon. Thus, in the repression model, the repressor Protein Protein Protein is inactive without a corepressor; in the induction model, the repressor is active A B C unless an inducer is present. In the absence of an inducer, the repressor binds to the opera- tor, preventing the binding of RNA poly- If one of the lac operon enzymes induced by lactose is lactose permease (which merase. When the inducer is present, the increases lactose entry into the cell), how does lactose initially get into the cell inducer binds to the repressor, inactivating it.
Ankle dorsiflexion with knee extension and with knee flexion are key measures in determining the source of equinus (Figure 3 kamagra effervescent 100mg with amex erectile dysfunction how young. The rotational alignment of the lower leg is best assessed in the prone position where the transmalleolar axis and the thigh–foot axis are measured (Figure 3 100 mg kamagra effervescent sale erectile dysfunction treatment los angeles. In the upper extremity, specific routine angle measurements have less direct impact on treatment decisions; therefore, the focus is on the functional problems encountered. Except for the basic measures of the hip, knee, and ankle, a large aspect of the physical examination of a child is directed at the spe- Figure 3. The child should be relaxed in cific functional impairments caused by the individual’s pattern of neurologic the supine position with the hips and knees involvement. The hip abduction is performed without much force, and the amount of each side is measured by palpating the iliac crest A to make sure that the pelvis is not rotating. Care is taken to measure each side hip ab- duction independent of the other side because tilting of the pelvis can mask significant sym- metry. Children less than 8 years old need an anteroposterior supine radiograph of the pelvis every 6 to 12 months if the hip abduc- tion is less than 45° on either side. Hip rotation should be assessed with the child prone with the hip extended. This is especially important because the ma- jor problem of hip malrotation during gait occurs with the hip near full extension. Exter- nal rotation is measured with the knee flexed 90° and making sure the pelvis remains level with the table surface (A). Internal rotation is assessed in the same way, but rotating in the opposite direction (B). Hip flexion is measured with the contralateral hip in extension and lordosis reduced to normal range. Total flexion is than measured without forceful further push toward flexion. Hip extension can be measured several ways, but the technique of dropping the contralateral leg off the end of the table works well for many children. This helps to control the lumbar lordosis, which is very dif- ficult to separate from a hip flexion contrac- ture or lack of hip extension. Managing the Child with Quadriplegic Pattern Cerebral Palsy Making the diagnosis in the child with quadriplegic pattern CP is not usu- ally difficult because of the severity of the neurologic involvement; however, this is the group in which one most often continues to try to find an etiology for the problem. There are physicians, especially neurologists, who do not want to give the diagnosis of CP. However, it is very helpful for the parents to be given a diagnosis, allowing them to relate to other families with simi- lar problems. Children with quadriplegic pattern involvement are most likely to have many associated medical problems. Coordinated medical care is especially important for these children. The orthopaedic problems in early and middle childhood revolve around getting children weight bearing and preventing hip dislocation. These children should start being followed by an orthopaedist at around 18 to 24 months 3. The popliteal angle is measured at the knee with the contralateral hip and knee in full extension. The hip on the side to be measured is then flexed to 90° and the knee slowly extended until the pelvis starts to move. This is the point when the angle should be measured. The measurement of the popliteal angle is not the angle at the point of maxi- mum knee extension because this only meas- ures how much the knee can extend with maximum pelvic rotation. Ankle dorsiflexion needs to be measured both with the knee in full extension as shown in this image, and the dorsiflexion should be measured with the knee flexed at least 45° to relax the gastrocnemius muscle. The measurement with the knee extended measures the length of the gastrocnemius muscle, and ankle dorsiflexion with the knee flexed measures the soleus length.
Fondaparinux stimulates the binding of ATIII to Factor Xa by 300-fold and is specific for Factor Xa inhibition generic 100mg kamagra effervescent otc impotence your 20s. Fonda- parinux does not affect thrombin or platelet activity order 100 mg kamagra effervescent otc erectile dysfunction 2015, and it is not an activating agent of platelets. Because fondaparinux does not bind to PF4, HIT is not a complication with this therapy. The drug (shown in blue) binds to ATIII, which induces a con- formational change such that Factor Xa can now bind to ATIII. Once Factor Xa binds, and is inactivated, the drug is released and can activate another molecule of ATIII. Direct thrombin inhibitors are based on the hirudin molecules, which were ini- tially discovered in leeches and other blood-sucking organisms. These organisms would not be able to feed if the blood clotted at the site of the puncture wound, so the organisms secrete thrombin inhibitors to prevent clotting from occurring. Hirudin treatment itself is dangerous in that formation of the hirudin–thrombin complex is irreversible, and use of the drug requires constant monitoring of the patient. Thus, to overcome this problem, rational drug design based on the hirudin structure was used, and a synthetic 20–amino acid peptide known as bivalirudin was synthesized. This agent has a high binding affinity and specificity for thrombin although its effects on thrombin are transient (not irreversible), making this a safer agent for long-term use. Selective inhibition of coagulation factors: advances in antithrombotic therapy. Seminars in Thrombosis and Hemostasis 2002;28:15–24. Update on selected inherited venous thrombotic disorders. The edema observed in patients with non-calorie protein malnutrition is due to which of the following? A recent surgery patient receiving warfarin therapy was found to be bleeding internally. The clotting process is impaired in this patient primarily because of which of the following? An inactivating mutation in which of the following proenzymes would be expected to lead to thrombosis, uncontrolled blood clotting? Classical hemophilia A results in an inability to directly activate which of the following factors? Hemophilia B results in an inability to directly activate which of the following factors? It receives 20 to 25% of the volume of blood leaving the heart each minute (the cardiac output) through the portal vein (which delivers absorbed nutrients and other substances from the gastrointestinal tract to the liver) and through the hepatic artery (which delivers blood from the general circulation back to the liver). Potentially toxic agents absorbed from the gut or delivered to the liver by the hepatic artery must pass through this metabolically active organ before they can reach the other organs of the body. The liver’s relatively large size (approximately 3% of total body weight) allows extended residence time within the liver for nutrients to be properly metabolized as well as for potentially harm- ful substances to be detoxified and prepared for excretion into the urine or feces. Among other functions, therefore, the liver, along with the kidney and gut, is an excretory organ, equipped with a broad spectrum of detoxifying mechanisms. It has the capacity, for example, to carry out metabolic conversion pathways as well as secretory systems that allow the excretion of potentially toxic compounds. Con- currently, the liver contains highly specific and selective transport mechanisms for essential nutrients that are required not only to sustain its own energy but to provide physiologically important substrates for the systemic needs of the organ- ism. In addition to the myriad of transport processes within the sinusoidal and canalicular plasma membrane sheets (see below), intracellular hepatocytic trans- port systems exist in organelles such as endosomes, mitochondria, lysosomes,as well as the nucleus. The sequential transport steps carried out by these organelles include (1) uptake, (2) intracellular binding and sequestration, (3) metabolism, (4) sinusoidal secretion, and (5) biliary excretion. The rate of hepatobiliary transport is determined, in part, by the rate of activity of each of these steps. The overall transport rate is also determined by such factors as hepatic blood flow, plasma protein binding, and the rate of canalicular reabsorption. The various aspects of the major metabolic processes performed by the liver have been dis- cussed in greater detail elsewhere in this text.
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