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When one allele is normal, and the counterpart is defective; it is called heterozygous. Genes on the same chromosome are linked; and the linkages are more pronounced in the nearby genes. It is characterized by the phenotypic expression of the disease, even if one allele is abnormal or in heterozygous state. When an affected heterozygote (Dd) marries a normal spouse (dd), half of the progeny can have the disease. Examples of diseases with autosomal dominant inheritance are chondrodystrophy (dwarfism) and some types of porphyrias. It is estimated that more than 6% of all infants born alive suffer from genetic diseases and 1% from chromosomal aberrations. Gregor Johann Mendel (1822-84), who was Abbot of Brun, described the principles of heredity in 1866. Genetic evolution is constrained by gene function, the structure of genetic networks, and population biology. Phenotype or a particular character is controlled by a pair of alleles located on a specified area on the chromosomes. If the disease is manifested only in homozygous state (not expressed in heterozygous condition), it is known as recessive transmission. For example, in a person suffering from sickle cell anemia, both the alleles for beta globin gene have mutated. In certain cases, the carrier state may be identified biochemically, then it is referred to as the trait of the disease. For example, in sickle cell trait, one beta globin gene (allele) is normal; while the other one is abnormal (carrier state). When both father and mother are carriers, onequarter of siblings express the disease (both alleles abnormal), another one-quarter of siblings are normal, and half of the children are carriers. If only one parent is carrier and the other is normal; then there will be no affected child, but 50% children are carriers. A few examples are phenylketonuria, albinism, galactosemia and sickle cell anemia. In the autosomal conditions, the disease occurs in both sexes with equal frequency. In a wedding between a normal male and a carrier female, the probabilities are that onequarter is male with disease; one-quarter is female carrier; one-quarter normal male and one-quarter normal female. If an affected male marries a normal female, male children will be normal, but all female children will be carriers, because they all inherit the abnormal X from their father. In X-linked recessive condition, normal X dominates over abnormal X; but abnormal X is expressed when present with Y. Hemophilia, glucose-6-phosphate dehydrogenase deficiency, pseudo-hypertrophic muscular dystrophy (Duchenne type), and red green color blindness are examples of sexlinked recessive inheritance. Population Genetics A law stating the frequency of abnormal genes in population was discovered in 1908 independently by Hardy (mathematician) and Weinberg (physician). Or, p2: 2pq: q2 ratio is maintained in all generations (the ratio of normal and abnormal gene is maintained in all generations). It is known that 1 in 20,000 live births is an albino, which is inherited recessively. The frequency of q of the recessive albino gene can be calculated as follows: q2 = 1/20,000. That means, spontaneous mutation is taking place on that gene in successive generations. Hence, malarial parasites do not multiply easily in heterozygous individuals (Chapter 22). Therefore, in the malarial endemic areas, the lethal nature of the gene in the homozygous state is counterbalanced by the advantage in heterozygous state. Marriages with Close-cousins are Inadvisable the probability of two carriers getting married is increased in consanguinous marriages. For example, phenylketonuria has an incidence of 1 in 25,000 in general population; but it is 13 / 25,000 in children of first cousin marriages. Transmission of mitochondrial genes ends with each son, because son does not pass the mitochondrial genes to his offspring.

The A chain (Glycine chain) has 21 amino acids and B (Phenyl alanine) chain has 30 amino acids. There is another intrachain disulphide bond between 6th and 11th cysteine residues of A chain. The species variation is restricted to amino acids in position 8, 9 and 10 in A chain and in C-terminal of B chain. The porcine insulin and human insulin are structurally similar, except the terminal amino acid in B chain (Thr Ala). Arrows = site of action of proteolytic enzymes 30 Textbook of Biochemistry; Section A: Chemical Basis of Life. For example, in HbA (normal hemoglobin) the 6th amino acid in the beta chain is glutamic acid; it is changed to valine in HbS (sickle cell anemia). Structure of alpha helix Insulin, bearing no antigenic difference from human Insulin will not produce antibodies in diabetic patients even after a long-term use. Biologically active insulin (2 chains) is formed by removal of the central portion of the pro-insulin before release. Primary Structure Determines Biological Activity A protein with a specific primary structure, when put in solution, will automatically form its natural three dimensional shape. Even a single amino acid change (mutation) in the linear sequence may have profound biological Box 4. Configuration and Conformation Configuration of a protein denotes the spatial relationship between particular atoms. Secondary and tertiary levels of protein structure are preserved by noncovalent forces or bonds like hydrogen bonds, electrostatic bonds, hydrophobic interactions and van der Waals forces. A hydrogen bond is a weak electrostatic attraction between one electronegative atom like O or N and a hydrogen atom covalently linked to a second electronegative atom. Electrostatic bonds (ionic bonds): Positive charges are donated by epsilon amino group of lysine, guanidinium group of arginine and imidazolium group of histidine. Negative charges are provided by beta and gamma carboxyl groups of aspartic and glutamic acids. Hydrophobic bonds are formed by interactions between nonpolar hydrophobic side chains by eliminating water molecules. The van der Waals forces are very weak, but collectively contribute maximum towards the stability of protein structure. Alpha helix Pauling (Nobel prize, 1954) and Corey described the alpha-helix and beta-pleated sheet structures of polypeptide chains in 1951. The alpha-helix is the most common and stable conformation for a polypeptide chain. In proteins like hemoglobin and myoglobin, the alpha-helix is abundant, whereas it is virtually absent in chymotrypsin. The polypeptide bonds form the back-bone and the side chains of amino acids extend outward. Left handed alpha helix is rare, because amino acids found in proteins are of L-variety, which exclude left handedness. Adjacent strands in a sheet can run in the same direction with regard to the amino and carboxy terminal ends of the polypeptide chain (parallel) or in opposite direction (anti parallel beta sheet). Beta-pleated sheet is the major structural motif in proteins like silk Fibroin (anti parallel), Flavodoxin (parallel) and Carbonic anhydrase (both). Beta bends may be formed in many proteins by the abrupt U-turn folding of the chain. Collagen helix It is a triple helical structure found in collagen (details in Chapter 52). Secondary structure denotes the configurational relationship between residues which are about 3-4 amino acids apart; or secondary level defines the organization at immediate vicinity of amino acids.

Partition Mechanism of F Plasmid: Two Plasmid Gene-Encoded Products and a Cis-acting Region are Involved in Partition, T. References 83 Timing of Initiation of Chromosome Replication in Individual Escherichia coli Cells, K. Induction and Autoregulation of ada, a Positively Acting Element Regulating the Response of Escherichia coli to Methylating Agents, P. Effect of Photoreactivation on Mutagenesis of Lambda Phage by Ultraviolet Light, F. RecA-mediated Cleavage Activates UmuD for Mutagenesis: Mechanistic Relationship between Transcriptional Derepression and Posttranslational Activation, T. Strand-Specific Mismatch Correction in Nuclear Extracts of Human and Drosophila melanogaster Cell Lines, J. Specialized Nucleoprotein Structures at the Origin of the Terminus Region of the Escherichia coli Chromosome Contains Two Separate Loci that Exhibit Polar Inhibition of Replication, T. It does not include disconnected regulatory sequences which are discussed below, that may lie hundreds or thousands of nucleotides away. Promoters from different prokaryotic genes differ from one another in nucleotide sequence, in the details of their functioning, and in their overall activities. In eukaryotic cells, the analog of such an unregulated system is a promoter that requires no auxiliary proteins bound to sites separated from the promoter. That other proteins should be involved is logical as the activities of some promoters have to be regulated in response to changing conditions in the cell or in the growth medium. Part of this chapter discusses measurements of the differences between promoters because this information ultimately should assist learning the functions of these auxiliary proteins. This property was sufficient to permit enzymologists to devise assays for detection of the enzyme in crude extracts of cells. After synthesis, the radioactive polymer was separated from the radioactive precursor nucleotides by precipitation of the polymer with acid, and the radioactivity in the polymer was determined with a Geiger counter. Several basic methods are used to quantitate the activities of specific promoters. Run-off transcription is another method that is often used for examining the activity of promoters. This permits the simultaneous assay of several promoters as well as nonspecific transcription. Assaying transcription from an in vitro reaction is relatively easy if purified proteins can be used. Obtaining the purified proteins is not so easy, however, since often their very purification requires assaying crude extracts for the transcriptional activity. In other words, what can be done to determine the biological role of the enzyme that can be detected and purified Such mutants exist in populations of sensitive cells at a frequency of about 10-7. Mutants of the first class are resistant because their cell membrane is less permeable to rifamycin than the membrane in wild-type cells. Since rifamycin-resistant cells now contain a rifamycin-resistant polymerase, it would seem that this polymerase must be the only type present in cells. We might be purifying and studying the first enzyme when we should be studying the naturally resistant polymerase. Therefore cells cannot contain a polymerase that is naturally resistant to rifamycin. A second possibility is that cells contain two types of polymerase and both are sensitive to rifamycin. Because mutants resistant to rifamycin can be isolated, both types of polymerase would then have to be mutated to rifamycin resistance. The probability of mutating both polymerases is the product of the probability of mutating either one. From other studies we know that the mutation frequency for such an alteration in an enzyme is on the other of 10-7. Unfortunately there is an imperfection in the reasoning leading to the conclusion that E.

More important, however, was the behavior of bacteria under conditions simulating the presence of a gradient in attractant. It is difficult to control a gradient in the concentration of an attractant around the cell, but it is likely that a cell detects not a spatial gradient but the change in the concentration of attractant from one time to the next. Therefore, Berg devised a system to vary the concentration of attractant with time. Alanine aminotransferase catalyzes the interconversion of alanine and -ketoglutarate to pyruvate and L-glutamate. Both alanine and 628 Chemotaxis glutamate are attractants, and therefore the reaction cannot be used to create or destroy total attractant. This problem can be overcome by using a mutant that is blind to alanine but not blind to glutamate. Then the enzyme-catalyzed reaction can be used to vary the concentration with time of attractant surrounding a cell. If alanine, -ketoglutarate, and alanine aminotransferase are put in the medium bathing the cell Alanine + -ketoglutarate Alanine aminotransferase Pyruvate + L-glutamate being observed, then the concentration of attractant, glutamate, increases with time. When the glutamate concentration is decreasing as a result of adding glutamate, pyruvate, and alanine aminotransferase to the bathing medium, the distribution of run lengths is the same as when attractant concentration remains constant. The technique of immobilizing a cell via its hook or flagellum has also been highly useful in characterizing chemotaxis responses. After such an immobilization, a microprobe containing attractant or repellent can be positioned near a cell, and application of a brief electrical pulse will drive a known amount of the chemical into the medium in the immediate area. If the concentration changes are within the linear response range of the cell, the response to a brief pulse of Figure 22. The microscope contains additional electronics that record the rotation of the bacterium. Pulser Microscope with water immersion lens Micropipette Tethered cell the Energy for Chemotaxis 629 No attractant Increasing attractant Figure 22. Any other function can be approximated as a series of impulses of appropriate magnitude, and the responses to each of these can be summed. Such a technique of circuit analysis is well known to electrical engineers, but it has not yet been widely applied to biochemical systems. All the experiments mentioned above show that cells modulate the duration of their intervals of smooth swimming. Such a modulation is sufficient for the cells to achieve a net drift up a gradient of attractant. When a cell is swimming up a gradient in attractant concentration, that is, experiencing an increase in attractant concentration, it decreases the chances of its tumbling. When the attractant is decreasing, the average run duration is the same as when the cell is in constant attractant concentration. These properties mean that cells drift up gradients in attractant concentration, that is, they undergo a biased random walk, taking lengthened steps when they are moving up the gradient. The Energy for Chemotaxis Application of genetic and biochemical methods has allowed determination of the energy source required for chemotaxis. On the other hand, the flagella originate in the cell membrane, and a substantial proton gradient exists across the inner membrane under most growth conditions. Therefore the direct source of energy could also derive from the membrane potential. Cells treated with arsenate are found to be motile, but they do not swim up gradients of attractants. Next, to investigate the role of the membrane potential, cells can be grown anaerobically. This blocks the usual means of generation of the membrane potential because the electron transfer chain becomes inactive owing to the lack of a terminal electron acceptor. Other experiments show that cells swim when transmembrane pH gradient or membrane potentials are generated artificially.

Phenylalanine is a precursor of tyrosine and together they lead to the formation of thyroxine or thyroid hormone and of adrenaline and noradrenaline which is converted into a neurotransmitter, a brain chemical which transmits nerve impulses. Phlorotannins are a class of polyphenolic compounds (tannins) derived from pholorglucinol (1,3,5-trihydroxybenzene). As a biological molecule, it is composed of phosphorus and oxygen and plays a major role in biological processes of many organisms. Phosphatidic acid is a major constituent of cell membranes and acts as a biosynthetic precursor for the formation of all acylglycerol lipids in the cell. A phospholipid comprising choline linked to phosphatidic acid; it is a major component of cell membranes and is localized preferentially in the outer surface of the plasma membrane. A phospholipid containing serine that is an important constituent of cell membranes and is localized preferentially in the inner surface of the plasma membrane. Synonym(s): arginine phosphate the biological role played by a material entity when bound by a receptor of the adaptive immune system. Also: Choline phosphate, N-Trimethyl-2aminoethylphosphonate, O-Phosphocholine, Phosphocholine, Phosphorylcholine. A compound of creatine and phosphoric acid occurring in muscle, being the most important storage form of high-energy phosphate, the energy source in muscle contraction. Phosphorylation also regulates the activity of proteins, such as enzymes, which are often activated by the addition of a phosphate group and deactivated by its removal (called dephosphorylation). Derivatives of phosphatidic acids in which the phosphoric acid is bound in ester linkage to a serine moiety. Also Serine Phosphoglyceride Quenching of chlorophyll fluorescence by oxidised Q, the electron acceptor of photosystem 2; includes qQ-quenching. A blue photosynthetic pigment found in some bacteria and algae which absorbs light in the 618nm range. Phycoerythrin is the metal-free red phycobilin pigment in a conjugated chromoprotein of red algae. They are found in plants, fungi, nematodes and all groups of algae including cyanobacteria. Phytochelatins act as chelators, and are important for heavy metal detoxification. Two molecules of the 20 carbon geranylgeranyl pyrophosphate are condensed in a tail-to-tail configuration to give the forty carbon phytoene, the first committed step in carotenoid biosynthesis. A member of the class of pterocarpans that is the 3-O-methyl ether of (+)-6a-hydroxymaackiain (the 6aR,12aR stereoisomer). A phytoalexin found in pods of garden peas (Pisum sativum) and other plants of the pea family, including Tephrosia candida. Platelets are disk-shaped, contain no hemoglobin, and are essential for the coagulation of blood and in maintenance of hemostasis. This class of compounds includes many substances that play important roles in both eukaryotic and prokaryotic cells, such as putrescine, cadaverine, spermidine, and spermine. A carbohydrate polymer that is formed from three or more molecules of simple carbohydrates. Examples of polysaccharides are dextrin, starch, glycogen, cellulose, gums, and inulin. Any of various heterocyclic compounds, derived from pyrrole, that occur universally in protoplasm, contain a central metal atom, and provide the foundation structure for hemoglobin, chlorophyll, and certain enzymes. Physiologically inactive substances that can be converted to active enzymes, specific precursor form is referred to as a procarboxypeptidase A. In the case of pancreatic carboxypeptidase A, the inactive zymogen form, pro-carboxypeptidase A, is converted to its active form - carboxypeptidase A - by the enzyme enteropeptidase. In the case of pancreatic carboxypeptidase B, the inactive zymogen form, pro-carboxypeptidase B, is converted to its active form - carboxypeptidase A - by the enzyme enteropeptidase. This mechanism ensures that the cells wherein procarboxypeptidase A is produced are not themselves digested.