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The -helix infantile spasms 2 month old cheap mefenamic 250 mg amex, -sheet muscle relaxant vitamins minerals generic 500 mg mefenamic with mastercard, and -bend (-turn) are examples of secondary structures commonly encountered in proteins muscle relaxant spray mefenamic 250 mg order. It is a spiral structure muscle relaxant dosage mefenamic 250 mg purchase without a prescription, consisting of a tightly packed, coiled polypeptide backbone core, with the side chains of the component amino acids extending outward from the central axis to avoid interfering sterically with each other (Figure 2. For example, the keratins are a family of closely related, fibrous proteins whose structure is nearly entirely -helical. They are a major component of tissues such as hair and skin, and their rigidity is determined by the number of disulfide bonds between the constituent polypeptide chains. In contrast to keratin, myoglobin, whose structure is also highly -helical, is a globular, flexible molecule (see p. Hydrogen bonds: An -helix is stabilized by extensive hydrogen bonding between the peptide-bond carbonyl oxygens and amide hydrogens that are part of the polypeptide backbone (see Figure 2. This insures that all but the first and last peptide bond components are linked to each other through intrachain hydrogen bonds. Hydrogen bonds are individually weak, but they collectively serve to stabilize the helix. Thus, amino acid residues spaced three or four residues apart in the primary sequence are spatially close together when folded in the -helix. Amino acids that disrupt an -helix: Proline disrupts an -helix because its secondary amino group is not geometrically compatible with the right-handed spiral of the -helix. Instead, it inserts a kink in the chain, which interferes with the smooth, helical structure. Large numbers of charged amino acids (for example, glutamate, aspartate, histidine, lysine, and arginine) also disrupt the helix by forming ionic bonds or by electrostatically repelling each other. Finally, amino acids with bulky side chains, such as tryptophan, or amino acids, such as valine or isoleucine, that branch at the -carbon (the first carbon in the R group, next to the -carbon) can interfere with formation of the -helix if they are present in large numbers. The surfaces of -sheets appear "pleated," and these structures are, therefore, often called -pleated sheets. When illustrations are made of protein structure, -strands are often visualized as broad arrows (Figure 2. Comparison of a -sheet and an -helix: Unlike the -helix, -sheets are composed of two or more peptide chains (-strands), or segments of polypeptide chains, which are almost fully extended. Note also that the hydrogen bonds are perpendicular to the polypeptide backbone in -sheets (see Figure 2. Parallel and antiparallel sheets: A -sheet can be formed from two or more separate polypeptide chains or segments of polypeptide chains that are arranged either antiparallel to each other (with the N-terminal and C-terminal ends of the strands alternating as shown in Figure 2. When the hydrogen bonds are formed between the polypeptide backbones of separate polypeptide chains, they are termed interchain bonds. A -sheet can also be formed by a single polypeptide chain folding back on itself (see Figure 2. In globular proteins, -sheets always have a righthanded curl, or twist, when viewed along the polypeptide backbone. They are usually found on the surface of protein molecules and often include charged residues. Glycine, the amino acid with the smallest R group, is also frequently found in -bends. Nonrepetitive secondary structure Approximately one half of an average globular protein is organized into repetitive structures, such as the -helix and -sheet. The remainder of the polypeptide chain is described as having a loop or coil conformation. These nonrepetitive secondary structures are not random, but rather simply have a less regular structure than those described above. Supersecondary structures (motifs) Globular proteins are constructed by combining secondary structural elements (that is, -helices, -sheets, and coils), producing specific geometric patterns or motifs. They are connected by loop regions (for example, -bends) at the surface of the protein. Supersecondary structures are usually produced by the close packing of side chains from adjacent secondary structural elements.

The allele frequency measures the proportion of chromosomes that contain a specific allele spasms 1983 youtube purchase mefenamic 500 mg otc. Each individual with the 1-1 genotype has two copies of allele 1 muscle relaxant non-prescription discount 500 mg mefenamic visa, and each heterozygote (1-2 genotype) has one copy of allele 1 muscle relaxant vocal cord cheap mefenamic 500 mg without a prescription. A convenient shortcut is to remember that the allele frequencies for all of the alleles of a given locus must add up to 1 spasms diaphragm hiccups mefenamic 500 mg fast delivery. Therefore, we can obtain the frequency of allele 2 simply by subtracting the frequency, of allele 1 (0. This relationship, expressed in the Hardy-Weinberg equation, allows one to estimate genotype frequencies if one knows allele frequencies, and Viceversa: the Hardy-Weinberg Equation In this equation: p = frequency of allele 1 (conventionally the most common, normal allele) q = frequency of allele 2 (conventionally a minor, disease-producing p2 = frequency of genotype 1-1 (conventionally homozygous normal) 2pq = frequency of genotype 1-2 (conventionally heterozygous) q2 = frequency of genotype 2-2 (conventionally homozygous affected) In most cases where this equation is used, a simplification is possible. Although the Hardy-Weinberg equation applies equally well autosomal dominant and recessive alleles, genotypes, and diseases, the equation is most frequen used with autosomal recessive conditions. She is aware that she has an autosomal recessive genetic disease that bas required her lifelong adherence to a diet low in natural protein with supplements of tyrosine and restricted amounts of phenylalanine. She asks her genetics professor about the chances that she would marry a man with the disease-producing allele. First, the frequency of carriers for this condition is much higher than the frequency of affected homozygotes, and second, an affected person would be identifiable clinically. If events are nonindependent, multiply the probability of one event by the probability of the second event, assuming that the first has occurred. It is the probability that he will be a carrier (1/50, event 1) multiplied by the probability that he will pass the diseasecausing gene along (1/2, event 2), assuming that he is a carrier. This principle can be applied to estimate the frequency of heterozygous carriers of an autosomal recessive mutation. This exercise demonstrates two important points: · the Hardy-Weinberg principle can be applied to estimate the prevalence ofheterozygous carriers in populations when we know only the prevalence of the recessive disease. In contrast, in Huntington disease (autosomal dominant), the number of triplet repeats corre-: lates much more strongly with disease severity than does heterozygous or homozygous status. Sex Chromosomes and Allele Frequencies When considering X-linked recessive conditions, one must acknowledge that most cases occur in hemizygous males (xY). In some cases, a new mutation can be introduced into a population when someone carrying the mutation is one of the early fo~nders of the community, this is referred to as a founder effect. As the community rapidly expands through generations, the frequency of the mutation can be affected by natural selection, by genetic drift (see below), and by consanguinity. Note the four evolutionary factors responsible for genetic variation in populations are: · Mutation · Natural selection Genetic drift · Gene flow Branched Chain Ketoacid Dehydrogenase Deficiency Branched chain ketoadd dehydrogenase deficiency (maple syrup urine disease) occurs in 1/176 live births in the Mennonite community of Lancastershire, Pennsylvania. The predominance of a single mutation (allele) in the branched chain dehydrogenase gene in this group suggests a common origin of the mutation. I Natural Selection Natural selection acts upon genetic variation, increasing the frequencies of alleles that promote survival, or fertility (referred to as fitness) and decreasing the frequencies of alleles that reduce fitness. Dominant diseases, in which the disease-causing allele is more readily exposed to the effects of natural selection, tend to have lower allele frequencies than, do recessive diseases, where the allele is typically hidden in heterozygotes. Mutation rates and founder effects act along with genetic drift to make certain genetic diseases more common (or rarer) in small, isolated populations than ill the world at large. Although genetic drift affects populations larger than a single family, this example illustrates two points: · When a new mutation or a founder effect occurs in a small population, genetic drift can make the allele more or less prevalent than statistics alone would predict. Genetic drift may then change allele frequencies and a new Hardy-Weinberg equilibrium is reached. Because of gene flow, populations located close to one another often tend to have similar gene frequencies. Gene flow can also cause gene frequencies to change through time: the frequency of sickle cell disease is lower in African Americans in part because of gene flow from other sectors of the u. Consanguinity and Its Health Consequences Consanguinity refers to the mating of individuals who are related to one another (typically, a union is considered to be consanguineous if it occurs between individuals related at the secondcousin level or closer). Statistically, Note Consanguineous matings are more likely to produce offspring affected with recessive diseases because individuals who share common ancestors are more liable to share disease-causing mutations. Dozens of empirical studies have examined the health consequences of consanguinity, particularly first-cousin matings.

These signs reflect impaired synthesis of collagen due to deficiencies of prolyl and lysyl hydroxylases muscle relaxant commercial mefenamic 250 mg buy on-line, both of which require ascorbic acid as a cofactor muscle relaxant 2mg buy 500 mg mefenamic with visa. Unlike collagen muscle relaxant yellow house buy mefenamic 250 mg on line, tropoelastin is not synthesized in a pro- form with extension peptides muscle relaxant neck mefenamic 500 mg purchase visa. Furthermore, elastin does not contain repeat Gly-X-Y sequences, triple helical structure, or carbohydrate moieties. After secretion from the cell, certain lysyl residues of tropoelastin are oxidatively deaminated to aldehydes by lysyl oxidase, the same enzyme involved in this process in collagen. However, the major cross-links formed in elastin are the desmosines, which result from the condensation of three of these lysine-derived aldehydes with an unmodified lysine to form a tetrafunctional crosslink unique to elastin. The mutations, by affecting synthesis of elastin, probably play a causative role in the supravalvular aortic stenosis often found in this condition. A number of skin diseases (eg, scleroderma) are associated with accumulation of elastin. It affects the eyes (eg, causing dislocation of the lens, known as ectopia lentis), the skeletal system (most patients are tall and exhibit long digits [arachnodactyly] and hyperextensibility of the joints), and the cardiovascular system (eg, causing weakness of the aortic media, leading to dilation of the ascending aorta). Most cases are caused by mutations in the gene (on chromosome 15) for fibrillin; missense mutations have been detected in several patients with Marfan syndrome. Fibrillin is a large glycoprotein (about 350 kDa) that is a structural component of microfibrils, 10- to 12-nm fibers found in many tissues. Fibrillin is secreted (subsequent to a proteolytic cleavage) into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide a scaffold for deposition of elastin. Of special relevance to Marfan syndrome, fibrillin is found in the zonular fibers of the lens, in the periosteum, and associated with elastin fibers in the aorta (and elsewhere); these locations respectively explain the ectopia lentis, arachnodactyly, and cardiovascular problems found in the syndrome. Other proteins (eg, emelin and two microfibril-associated proteins) are also present in these microfibrils, and it appears likely that abnormalities of them may cause other connective tissue disorders. The fibronectin receptor interacts indirectly with actin microfilaments (Chapter 49) present in the cytosol (Figure 48­5). A number of proteins, collectively known as attachment proteins, are involved; these include talin, vinculin, an actin-filament capping protein, and -actinin. It consists of two identical subunits, each of about 230 kDa, joined by two disulfide bridges near their carboxyl terminals. The integrins are heterodimers, containing various types of and polypeptide chains. In that structure, the basal lamina is contributed by two separate sheets of cells (one endothelial and one epithelial), each disposed on opposite sides of the lamina; these three layers make up the glomerular membrane. Laminin (about 850 kDa, 70 nm long) consists of three distinct elongated polypeptide chains (A, B1, and B2) linked together to form an elongated cruciform shape. The collagen interacts with laminin (rather than directly with the cell surface), which in turn interacts with integrins or other laminin receptor proteins, thus anchoring the lamina to the cells. The relatively thick basal lamina of the renal glomerulus has an important role in glomerular filtration, regulating the passage of large molecules (most plasma proteins) across the glomerulus into the renal tubule. On the other hand, only a small amount of the protein albumin (69 Mutations in gene (on chromosome 15) for fibrillin, a large glycoprotein present in elastin-associated microfibrils Abnormalities of the structure of fibrillin Structures of the suspensory ligament of the eye, the periosteum, and the media of the aorta affected Ectopia lentis, arachnodactyly, and dilation of the ascending aorta Figure 48­2. Seven functional domains of fibronectin are represented; two different types of domain for heparin, cell-binding, and fibrin are shown. Also not shown is the fact that fibronectin is a dimer joined by disulfide bridges near the carboxyl terminals of the monomers. This is explained by two sets of facts: (1) the pores in the glomerular membrane are large enough to allow molecules up to about 8 nm to pass through. These negative charges repel albumin and most plasma proteins, which are negatively charged at the pH of blood. The normal structure of the glomerulus may be severely damaged in certain types of glomerulonephritis (eg, caused by antibodies directed against various components of the glomerular membrane). A number of them have been characterized and given names such as syndecan, betaglycan, serglycin, perlecan, aggrecan, versican, decorin, biglycan, and fibromodulin. They vary in tissue distribution, nature of the core protein, attached glycosaminoglycans, and function. The amount of carbohydrate in a proteoglycan is usually much greater than is found in a glycoprotein and may comprise up to 95% of its weight.

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Diseases

• Phocomelia thrombocytopenia encephalocele
• Ablepharon macrostomia syndrome
• Oral lichen planus
• Nut allergy
• Thalassemia major
• Myxoid liposarcoma
• Narcissistic personality disorder
• Exostoses
• Tricho odonto onycho dermal syndrome

References

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