By T. Gunock. Geneva College. 2017.
Cushing’s syn- gogues (stimulants to secretion) include drome is often caused by excessive doses of synthetic GCs used to treat a variety of nutritional factors generic orlistat 120 mg on line; the patient’s level of activity cheap orlistat 120mg on line, consciousness, and stress; and cer- disorders because of their potent anti-inflammatory effects (iatrogenic Cushing’s tain drugs. Vigorous fest by the significant incidence of diabetes mellitus (25%) and impaired glucose tol- exercise, stage III–IV sleep, psychological erance (33%) in patients with acromegaly, such as Sam Atotrope. Yet, under normal and physical stress, and levodopa, clonidine, circumstances, physiologic concentrations of GH (as well as cortisol and thyroid hor- and estrogens also increase GH release. This “proinsular” effect is strate the autonomous hypersecretion of GH probably intended to act as a “brake” to dampen any potentially excessive “contrain- involves giving the patient an oral glucose sular” effects that increments in GH and the other counterregulatory hormones exert. A sudden rise in blood glucose sup- presses serum GH to 2 ng/mL or less in nor- mal subjects, but not in patients with active acromegaly. BIOCHEMICAL COMMENTS If one attempts to demonstrate auto- nomous hypersecretion of GH in a patient Most hormones are present in body fluids in picomolar to nanomolar suspected of having acromegaly, therefore, amounts, requiring highly sensitive assays to determine their concentration in before drawing the blood for both the basal the blood or urine. Radioimmunoassays (RIAs), developed in the 1960s, use (pre-glucose load) serum GH level and the an antibody, generated in animals, against a specific antigen (the hormone to be meas- post-glucose load serum GH level, one must ured). Determining the concentration of the hormone in the sample involves incubat- be certain that the patient has not eaten for ing the plasma or urine sample with the antibody and then quantifying the level of anti- 6–8 hours, has not done vigorous exercise for at least 4 hours, remains fully awake dur- gen–antibody complex formed during the incubation by one of several techniques. A standard curve is prepared, using a set amount of the antibody and vari- GH secretion for at least 1 week. In addition to Under these carefully controlled circum- a known concentration of the unlabeled hormone, each tube contains the same stances, if both the basal and postsuppres- small, carefully measured amount of radiolabeled hormone. The labeled hormone sion serum levels of the suspect hormone and the unlabeled hormone compete for binding to the antibody. The higher the are elevated, one can conclude that amount of unlabeled hormone in the sample, the less radiolabeled hormone is autonomous hypersecretion is probably bound. At this point, localization proce- patient’s blood or urine, containing the unlabeled hormone to be measured, is incu- dures (such as an MRI of the pituitary gland in an acromegalic suspect) are performed to bated with the immobilized antibody in the presence of the same small, carefully further confirm the diagnosis. The amount of radiolabeled hormone bound to the antibody is determined, and the standard curve is used to quantitate the amount of unlabeled hormone in the patient sample.
Glycosylation Oligosaccharides (small carbohydrate chains) are bound to proteins by either N- linkages or O-linkages (see Fig generic 60 mg orlistat with mastercard. N-linked oligosaccharides are found attached to cell surface proteins buy generic orlistat 60mg online, where they protect the cell from proteolysis or an immune attack. In contrast, an O-glycosidic link is a common way of attaching oligosac- charides to the serine or threonine hydroxyl groups in secreted proteins. The intra- cellular polysaccharide glycogen is attached to a protein through an O-glycosidic linkage to a tyrosine. Fatty Acylation or Prenylation Many membrane proteins contain a covalently attached lipid group that interacts hydrophobically with lipids in the membrane. Palmitoyl groups (C16) are often attached to plasma membrane proteins, and the myristoyl group (C14) is often Adenylyl cyclase is posttranslation- attached to proteins in the lipid membranes of intracellular vesicles (see Fig. The farnesyl (C15) or geranylgeranyl group (C20) are synthesized from an oligosaccharide chain attached the five-carbon isoprene unit (isopentenyl pyrophosphate, see Fig. These are attached in ether linkage to a specific of the isozymes contain serine residues on cysteine residue of certain membrane proteins, particularly proteins involved in the intracellular portion of the chain that regulation. Regulatory Modifications Phosphorylation, acetylation, and adenosine diphosphate (ADP)-ribosylation of specific amino acid residues in a polypeptide can alter bonding by that residue and change the activity of the protein (see Fig. Phosphorylation of an OH group on serine, threonine, or tyrosine by a protein kinase (an enzyme that trans- fers a phosphate group from ATP to a protein) introduces a large, bulky, nega- tively charged group that can alter the activity of a protein. Reversible acetylation occurring on lysine residues of histone proteins in the chromosome changes their 86 SECTION TWO / CHEMICAL AND BIOLOGICAL FOUNDATIONS OF BIOCHEMISTRY Carbohydrate addition O-glycosylation: OH of ser, thr, tyr, N-glycosylation: NH2 of asn O H O CH2 CH2 R O R O ser asn N N AC AC Lipid addition Palmitoylation: Internal SH of cys Myristoylation: NH of N-terminal gly O O O H3C (CH2)14 C S CH2 H3C (CH2)12 C N CH2 C H cys gly Prenylation: SH of cys O Cys C OCH3 SH O CH3 CH3 Cys C OCH3 CH3 C (CH2 CH2)2 H Regulation Phosphorylation: OH of ser, thr, tyr Acetylation: NH2 of lys, terminus O O CH O P O– CH C N CH CH CH CH 2 3 2 2 2 2 H O– ser arg ADP-ribosylation: N of arg, gln; S of cys + O O NH2 H Adenine CH2 P CH2 N C CH2 CH2 CH2 O – – O O O arg H HO OH HO OH Modified amino acids Oxidation: pro, lys Carboxylation: glu O N CH C CH2 pro H2 2 glu C CH –COO COO– H 4-Hydroxyproline γ–Carboxyglutamate residue Fig. Posttranslational modifications of amino acids in proteins. Some of the com- mon amino acid modifications and the sites of attachment are illustrated. Because these modifications are enzyme-catalyzed, only a specific amino acid in the primary sequence is altered. In N-glycosylation, the attached sugar is usually N-acetylglucosamine (N-Ac). CHAPTER 6 / AMINO ACIDS IN PROTEINS 87 interaction with the negatively charged phosphate groups of DNA.
Glucuronic acid is formed by oxidation of the glucose terminal OH group buy orlistat 60mg otc. Sorbitol purchase orlistat 120 mg mastercard, a sugar alcohol, is formed by reduction of the glucose aldehyde group. N- AND O-GLYCOSIDIC BONDS The hydroxyl group on the anomeric carbon of a monosaccharide can react with an –OH or an –NH group of another compound to form a glycosidic bond. The link- age may be either or , depending on the position of the atom attached to the anomeric carbon of the sugar. N-glycosidic bonds are found in nucleosides and nucleotides. For example, in the adenosine moiety of ATP, the nitrogenous base adenine is linked to the sugar ribose through a -N-glycosidic bond (Fig. In contrast, O-glycosidic bonds, such as those found in lactose, join sugars to each other or attach sugars to the hydroxyl group of an amino acid on a protein. DISACCHARIDES, OLIGOSACCHARIDES, AND POLYSACCHARIDES A disaccharide contains two monosaccharides joined by an O-glycosidic bond. Lac- tose, which is the sugar in milk, consists of galactose and glucose linked through a (1S 4) bond formed between the –OH group of the anomeric carbon of galac- tose and the hydroxyl group on carbon 4 of glucose (see Fig. Oligosaccharides contain from 3 to roughly 12 monosaccharides linked together. They are often found NH2 C N N C Adenine CH O–Glycosidic bond HC C β–1,4 linkage N O O O N–Glycosidic HOCH2 HOCH2 – bond O O O P O P O P OCH2 HO H H O H H O– O– O– O H OH H H OH H OH H H Ribose H H H OH H OH HO OH Lactose ATP (Galactose–β(1 4)–glucose) HOCH2 O H H H 1 O–Glycosidic bond O OH H O α–1,6 linkage H OH 6CH2 HOCH2 O O H H H H H H 1 4 O O O OH H OH H H OH H OH α–1,4 linkage Starch Fig. Adenosine triphosphate (ATP) contains a , N-glycosidic bond. CHAPTER 5 / STRUCTURES OF THE MAJOR COMPOUNDS OF THE BODY 63 attached through N- or O-glycosidic bonds to proteins to form glycoproteins (see Chapter 6).
These children complain of pain in the dorsum of the interphalangeal joint of the hallux order orlistat 120mg amex. Treatment For children with extended toes in whom there is no other foot deformity and the interphalangeal joint is extended or neutral cheap 60mg orlistat with visa, the extensor hallucis longus is tenodesed to the tibialis anterior or to the proximal end of the first metatarsal. The tendon of the extensor hallucis longus is left intact and at- tached distally, which will prevent the hallux from dropping into flexion, but now the active component of the extensor hallucis longus can function as an ankle dorsiflexor. If the extended metatarsal phalangeal joint is associated with a flexed interphalangeal joint, tenotomy of the flexor tendon at the metatarsal pha- langeal joint level with fusion of the interphalangeal joint is recommended. The classic Jones transfer of the flexor hallucis longus to the dorsum of the hallux is not routinely recommended because this muscle has to be very spas- tic to cause the deformity initially; therefore, after a transfer, it may cause more flexion of the hallux than desired. Minor Toes The most common minor toe problem in children with CP is clawing of the toes. This clawing is a direct effect of the spasticity, and sometimes after transfer of the tibialis anterior or lengthening of the tibialis anterior with gastrocsoleus lengthening, the overactive toe flexors and toe extensors be- come more evident. The clawing is especially severe in children or adoles- cents who have correction of severe equinus because the toe flexors will also be contracted in these situations. Most of these children have a clawing that involves flexion of the metatarsal phalangeal joint and interphalangeal joint; however, some individuals develop cock-up toes with extension of the meta- tarsal phalangeal joint and flexion of the interphalangeal joints. This cock-up toe is a toe collapse caused by overpull of both the flexor and the extensor muscles, which most commonly is seen in ambulators. Natural History Most of the minor toe deformities cause few problems in children; however, by adolescence, these fixed deformities may start causing irritation by rubbing on the inside of shoes. Treatment No treatment is required if mild toe contractures are easily corrected pas- sively after lengthening of the gastrocnemius or tendon Achilles. However, care should be taken in cast immobilization to make sure there is a good sup- portive toe plate past the tips of the toes, and that some stretch is placed on the toe flexors by elevating the toe plate slightly. Ankle-foot orthotics should always have toe plates to prevent the clawing response, which is especially strong if the brace ends in the middle of the toes. We have seen casts applied that ended with a short toe plate in which the children clawed over the end of the cast until deep ulcers developed on the plantar surface of the toes. If the toe cannot be easily brought to neutral after lengthening of the ten- don Achilles, an intramuscular lengthening of the flexor hallucis longus and 788 Cerebral Palsy Management the flexor digitorum longus should be performed. This lengthening can be done through the same posterior incision through which the tendon Achilles lengthening was performed.