Amino acid substitutions variants

Given a large population of individuals, a considerable number of sequence variants can be found for a protein. These variants are a consequence of mutations in a gene (base substitutions in DNA) that have arisen naturally within the population. Gene mutations lead to mutant forms of the protein in which the amino acid sequence is altered at one or more positions. Many of these mutant forms are neutral in that the functional properties of the protein are unaffected by the amino acid substitution. Others may be nonfunctional (if loss of function is not lethal to the individual), and still others may display a range of aberrations between these two extremes. The severity of the effects on function depends on the nature of the amino acid substitution and its role in the protein. These conclusions are exemplified by the more than 300 human... 

Viruses that contain amino acid substitutions in the sialidase that impart resistance to the developed inhibitors have been isolated from serial passage of virus in the presence of drug in cell culture and from the clinical setting (reviewed in McKimm-Breschkin 2000 Zambon and Hayden 2001 Cinatl et al. 2007a Reece 2007). In addition, influenza B virus variants with reduced drug sensitivity have been isolated from previously untreated patients (Hurt et al. 2006 Hatakeyama et al. 2007). The types of mutations that are observed are sub-type specific. The mutations present in variants isolated from clinical samples are shown in Table 1, and their locations within the sialidase active site are shown diagrammatically in Fig. 9. 

Many are distinguished from Hb-A by electrophoretic or chromatographic methods The number and types of abnormal hemoglobins that have been discovered thus far are Indeed overwhelming At the latest count (December, 1974) at least 135 3-chaln variants, 72 a-chaln variants, 8 6-chaln variants, and 11 y-chaln variants have been found These Include variants with single amino acid substitutions (the majority), variants with two substitutions (the 6-chaln variants, Hb-C-Harlem and Hb-Arllng-ton Park), variants with deletion of one or more residues... 

Variants Amino Acid Substitution Spectroscopic Maxima at pH 7.1 Velocity of -CN Reactivity and CN-Ferrl-Hb Spectrum... 

Sata, F. et al. (2000). CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12 evidence for an allelic variant with altered catalytic activity. Clin. Pharmacol. Ther., 67,48-56. 

F5. Fujii, H., Krietsch, W. K. G., and Yoshida, A., A single amino acid substitution (Asp -> Asn) in a phosphoglycerate kinase variant (PGK Miinchen) associated with enzyme deficiency. J. Biol. Chem. 255,6421-6423 (1980). 

F14. Fujii, H., Kanno, H., and Miwa, S., Expression and enzymatic characterization of the glucose phosphate isomerase variants with diverse single amino acid substitutions. Blood 88 (Suppl. 1), 306a (1996). 

K7. Kanno, H Fujii, H and Miwa, S., Low substrate affinity of pyruvate kinase variant (PK Sapporo) due to a single amino acid substitution (426Arg- Gln) associated with hereditary hemolytic anemia. Blood 81,2439-2441 (1993). 

Gene Subunit Amino acid substitution in polymorphic variants K, [Ethanol] [mM] Turnover rate [min-1] Three- dimensional structure... 

When chromatographic resolution of species based on modifications located at the protein surface is desired, it may be advisable to use conditions that favor retention of native conformation.17 Here, the standard acidic conditions described in the preceding text may be inappropriate, and mobile phases buffered near neutrality may be required. Buffers based on ammonium acetate, ammonium bicarbonate, and triethylammonium phosphate may prove more useful in resolving polypeptide variants with differing posttranslational modifications, amino acid substitutions, or oxidation and deamidation products. The addition of more hydro-phobic ion-pairing agents may be needed to obtain polypeptide retention, and a variety of alkyl sulfonates and alkyl amines have been described for specific applications.17... 

The TBXA2R gene splice variants result, therefore, in protein structures with distinct functions. An amino acid substitution that is deleterious in one splice isoform, however, may only be a polymorphic marker in another. This phenomenon... 

Heterozygous carriers of functionally relevant mutations usually present with HDL cholesterol levels that are frequently below the fifth percentile. As would be expected, apoA-I levels are also frequently below the fifth percentile (i.e., < 1.05 g/1 and < 1.1 g/1 in Caucasian men and women, respectively). In most cases, heterozygous carriers of apoA-I variants do not present with specific clinical symptoms. An important exception are some structural apoA-I variants with amino acid substitutions in the amino terminus, which have been detected in patients with familial amyloidosis of the liver, the intestine, the kidney, the heart, peripheral nerves, and in the skin. In addition, some apoA-I variants like apoA-I L178P or L159P have been associated with increased risk of premature coronary heart disease or enhanced progression of carotid intima media thickness, whereas others did not show this association, or were even claimed to have reduced cardiovascular risk and advocated as possible agents for the treatment or prevention of atherosclerosis (notably apoA-I R173CMiiano) [22,43,53]. 

Amino acid composition. The approximate amino acid composition of the main caseins is shown in Table 4.4. Amino acid substitutions in the principal genetic variants can be deduced from the primary structures (Figures 4.9-4.12). Four features of the amino acid profile are noteworthy ... 

Figure 4.9 Amino acid sequence of bovine atl -casein, showing the amino acid substitutions or deletions in the principal genetic variants (from Swaisgood, 1992).

Although 10% of all PCR-generated variants contained frameshift mutations (leading to early termination of translation), the mutation frequency of 0.93 % on the nucleotide level yielded 1.78% amino acid substitutions after translation. Because multiple substitutions within a single codon are extremely rare, a proportion of 30% of all mutations were silent that is, they did not influence the amino acid sequence. 

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