Genetic Control of metabolism

Gene Enzyme RelationThe understanding of correlationship between genes and phenotype of an organism requires a consideration of the consequences of gene malfunction, since the expression of abnormal gene effect is a major source of the information gained concerning normal gene function. The groundwork for a functional relationship between genes and enzymes was laid in 1902 when Bateson reported that a rare human defect alcaptonuria was inherited as a recessive trait. Then in 1909, Garrod, in his book, "Inborn errors of metobolism" suggested relationship between genes and specific chemical reactions. Alcaptonuria was among the heritable diseases with which he dealt at length. But his remarkable piece of work remain unnoticed until 1940 when Beadle, Tatum, Epbrussi and other geneticists had got modern understanding of gene action by performing experiments on Neurospora and Drosophila.

They found that mutational changes of genes can be related to losses of specific enzymes. This concept was widely known as "one gene one enzyme hypothesis." This hypothesis can be understood well by knowing the phenomenon of metabolic block.

Metabolic Block

A biosynthetic pathway, often, requires more than two enzymes and each enzyme is specified by a single gene. If, there occurs any mutation in any gene, then either the production of normal enzyme will be ceased or a defective enzyme will be produced. This defective enzyme instead of determining the normal phenotype, will determine an abnormal, defective or mutant phenotype. Such mutant genes, which alter the enzymes of a biosynthetic pathway in such a manner that a defective phenotype is resulted are said to a cause "metabolic blocks." The metabolic block have been found to cause various abnormal phenotypes or diseases in variety of organisms and provide best opportunities to understand the relation of genes with enzymes and phenotypes of an organism more properly.
Thus, the mutations in genes that control sequential biological steps have proved to be invaluable for "dissecting" the number and order of reactions in given biosynthetic pathway. In particular, a field of study known as biochemical genetics has combined genetics and biochemistry to elucidate the nature of metabolic pathways, most notably in haploid organisms whose growth requirements are known and whose gene expression is not complicated by allelic interactions.

Approach of Biochemical Genetics -

The approach followed in biochemical genetics is to assemble a collection of mutant strains that cannot synthesize a particular component and thus require it for growth. These strains are subjected to complementation tests to estimate how many separate genes are involved, and the genes are mapped to determine their relationships.

Strains in a given complementation group are then tested for their ability to grow when supplied with known metabolic precursors of the final component. It then can grow in the presence of a certain precursor, they must suffer from a genetic lesion affecting a step before the synthesis of that precursor. I instead they cannot grow when a certain precursor is supplied, the genetic lesion must affect a step that follows the synthesis of that precursor.

Phenotypic Expression of Genes

Biochemical Genetics DNA of genes has two essential functions: (i) replication or self-reproduction and (ii) intervention in phenogenesis. The phenogenesis is a mechanism by which the phenotype of an organism is realized or produced under the control of DNA in a given environment which includes not only external factors such as temperature and the amount or quality of light, but also internal factors such as hormones and enzymes. The phenotype of an organism is not the direct outcome of action of its DNA, but is the result of various embryological and biochemical activities of its cells from zygotic to multicellular stage. All these cellular activities basically involve a variety of structural and functional or enzymatic proteins. Enzymatic proteins or enzymes perform catalytic functions, causing the splitting or union of various cellular molecules. All of the biochemical reactions of cell constitute the subject of intermediary metabolism.

Each reaction of intermediary metabolism occurs as stepwise conversions of one substance into another. All the steps which transform a precursor substance to its end product which is ultimately expressed in to a structural or functional phenotypic trait, constitute a biosynthetic pathway. Each step of a biosynthetic pathway is catalyzed by a specific enzyme which in its turn being produced by a specific gene. It has become clear now that ( 1) DNA of genes itself, does not have an enzymatic character, therefore, does .not involve directly in a biosynthetic pathway of cell; (2) between the gene and final product or between the gene and enzyme there is a long, tortuous path; (3) the immediate or primary gene product is a kind of RNA called mRNA (messenger ribonucleic acid) which is complementary to the DNA of the genes and which controls the assemblage of the amino acids to form enzymes, at the surface of cytoplasmic ribosomes. Thus, to produce a particular phenotypic trait DNA transcribes mRNA which translates into an enzymatic or structural protein which ultimately produces a phenotypic trait by the process of phenogenesis. The relationship between genes and enzymes had been suspected very early in the history of biochemical or physiological genetics.

Phenylalanine Metabolism in Man-

The metabolism of the aromatic amino acids-phenylalanine and tyrosine in man provides a best example of a gene-controlled, enzyme catalyzed biochemical reaction. In man, phenylalanine is an essential amino acid which must be supplied in the dietary proteins. Once in the body, phenylalanine may follow any of three paths. It may be (1) incorporated into cellular proteins, (2) converted to phenylpyruvic acid, or (3) converted to tyrosine. The conversion of phenylalanine into tyrosine takes place in the presence of phenylalanine hydroxylase enzyme, in the liver cells. Tyrosine is converted in turn to 3-4-dihydroxy phenylalanine (nick-named DOPA) by another enzyme and DOPA serves as a precursor for the hormones adrenaline and noradrenaline and for the black pigment, melanin.

Tyrosine itself serves as a precursor of the hormones thyroxine and triiodothyronine. Excess tyrosine is degraded to carbon dioxide and water by a series of steps which involves the formation of p-hydroxyphenyl pyruvate, 2-5 dihydroxy phenyl pyruvate, homogentisic acid, maleylacetoacetic acid, fumaryl acetoacetic acid and fumaric and acetoacetic acid. Excess phenylalanine is degraded by a series of steps to compounds which include phenylpyruvic acid and phenyl lactic acid.

Genetic disorders of the phenylalanine metabolism and resulted diseases-

Five rare diseases in man result from improper functioning of five enzyme systems (i.e., metabolic blocks) involved in the metabolism of phenylalanine, tyrosine and their derivatives. All of these diseases have been found to be due to mutant, autosomal recessive genes in homozygous conditions. These diseases are following:

1.Phenylketonuria-

Persons with genotype pp fail to produce enzyme phenylalanine hydroxylase (parahydroxylase) with the result that phenylalanine fails to convert into tyrosine and consequently, the concentration of phenylalanine rises in the blood plasma, cerebrospinal fluid and urine. The urine of phenylketonuric (PKUJ patient contains (in addition to phenylalanine) elevated amounts of phenylpyruvic acid, phenyl lactic acid and other derivatives of phenylalanine. PKU patients have light pigmentation and are physically and mentally retarded. The feeble mindedness in PKU patients is thought to -be due to an impairment of the brain tissues by the phenylpyruvic acid in the cerebro-spinal fluid.

2. Alkaptonuria-

The persons with genotype hh fail to produce the enzyme homogentisic acid oxidase which catalyzes the oxidation of homogentisic acid. Therefore, in them, normal oxidation of homogentisic acid into water and carbon dioxide does not occur and large amounts of homogentisic acid are excreted in the urine, which turn black upon exposure to the air. Moreover, the homogentisic acid accumulate in the body and become attached to the collagen of cartilage and other connective tissues, due to which, the ear and sclerae are stained black. Persons with such phenotypic abnormalities are said to have alkaptonuria disease.

3. Tyrosinosis-

The recessive gene, t in its homozygous condition, blocks the conversion of p-hydroxyphenylpyruvate into 2, S-dihydroxyphenyl pyruvate. This leads to the accumulation of tyrosine, excesses of which are excreted via the urine. This condition is called tyrosinosis. It is reported in only one human and cause no harmful effect.

A. Phenylketonuria
B. Tyrosinosis
C. Alkaptonuria
D. Goitrous Cretinism
E. Albinism

4. Goitrous cretinism-

The persons with cc genotype fail to produce the enzyme which is required for the conversion of tyrosine into thyroxine and triiodothyronine hormones in their thyroid glands. This condition is called goitrous cretinism which is accompanied by a considerable degree of physical and mental retardation and hypertrophy of thyroid gland.

5. Albinism-

The persons with recessive aa genotype lack in the tyrosinase enzyme system which is required for the conversion of 3, 4-dihydroxyphenyl alanine (DOPA) into melanin pigment inside the melanocytes. In an albino patient melanocytes are present in normal numbers in their skin, hairs, iris, etc., but lack in melanin pigment.

Eye Pigmentation in Drosophila -

The metabolism of Drosophila eye pigment (ommochrome) xanthommatin suggests a gene-enzyme-relationship. The dull red compound eyes of wild type Drosophila is produced by deposition of brown pigment (xanthommatins) in the-periphery of each ommatidiun and red pigment (drosopterins) in the centre of each ommatidium of compound eye. The xanthommatins are the end products of the metabolism of the amino acid tryptophan which is taken by Drosophila along with food as an essential amino acid. To form xanthommatin, tryptophan first is converted into formylkynurenine, which converts into kynurenine, and the kynurenine by undergoing via hydroxy kynurenine compound forms xanthommation. Four recessive nonallelic genes are known which block the synthesis of the xanthommatin but which have no effect upon the formation- of the drosopterins.

As a consequence all the mutant insects are characterized by compound eyes which have a bright red colour. Individuals homozygous for the sex-linked gene vermilion (v) fail to convert tryptophan into formylkynurenine and so accumulate tryptophan.Individuals homozygous for the second chromosomal gene circular (cn) cannot convert kynurenine into hydroxy kynurenine and as a consequence, they accumulate kynurenine. Individuals homozygous for the third chromosomal mutants scarlet (st) or cardinal (cd) produce the water soluble compounds, formylkynurenine, kynurenine and hydroxy kynurenine.