Tautomerism and Mutations: Impacts on Nucleic Acids and Proteins, Assignments of Molecular biology

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WAJEEHA AKRAM MPHIL MOLECULAR MEDICINE DEPARTMENT OF BIOCHEMISTRY & MOLECULAR BIOLOGY AMC, NUMS

Tautomeris

m &

Mutation’s

impacts

TAUTOMERS

 Tautomers are the alternate forms of

bases and are produced by

rearrangements of electrons and

protons in the molecules.

 It is a structural isomer of some

compound, that is interconvertible and

thus exists at equilibrium with the

standard, “normal” molecule.

TAUTOMERIZATION

• (^) Due to tautomerisation the amino (-NH

group of cytosine and adenine is converted

into imino(-NH) group and likewise keto

(C=0) of thymine and guanine is converted

to enol group (-OH).

 Problems occur when the nitrogenous

bases in DNA tautomerize. Tautomeric

thymine pairs with normal guanine and

cytosine with adenine. Such pairing of

nitrogenous bases are known as unusual

base pair.

 The tautomer form of the base hydrogen-

bonds to an incorrect base, and so the base

laid down during replication will be wrong,

inducing a mutation (if this mismatch is

preserved through another round of

replication).

 This causes transitions (because the class

of nitrogenous base is preserved).

Functional Impact of Mutation Mutations are also classified by their impact on protein function.

• (^) Complete loss of the protein- : null, loss-of-function, amorph
• (^) Reduction of protein’s ability to work: hypomorph, reduction-of-function Loss of Function
• (^) Increase in the protein’s function : hypermorph, gain-of-function
• (^) A protein that interferes with the wild-type protein’s function : antimorph, dominant negative
• (^) Acquisition of a new function (or ectopic expression of the function ): neomorph, dominant gain-of-function Gain of Function

Null Mutation  (^) A mutation that completely eliminates gene function, usually because the gene has been deleted is known as Null mutation.  (^) If the gene is essential the null mutation is lethal.

Hyper-morphic  (^) When the mutation in a particular gene increases the phenotypic expression of the gene (enhancing the protein product) is called hyper-morphic.  (^) Hypermorphic mutation is inherited in the dominant trait inheritance fashion.  (^) Hereditary pancreatitis (mutation that causes a digestive enzyme, trypsin, to become aberrantly active inside the pancreas).

Anti-morphic  (^) The defective gene interferes with the function of the wild- type copy.  (^) Dominant negative (opposite to wild type).  (^) Increasing wildtype gene function reduces the phenotypic severity of an antimorph  (^) Marfan syndrome (Defective Fibrillin-1 proteins disrupt the integrity of microfibrils in the extracellular matrix).

Haplo-insufficiency  (^) Haploinsufficiency-a single copy of the standard (so-called wild-type) allele at a locus in heterozygous combination with a variant allele is insufficient to produce the standard phenotype.  (^) Haploinsufficiency may arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it produces little or no gene product (often a protein).  (^) Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype.  (^) Ehlers Danlos

Overview Category Alternative function Wild type Referent gene expression, full ("normal"), expression of parent allele Amorph Dysfunctional, with null expression Hypomorph Reduced, or partial reduced gene activity Hypermorph Increased or partial increased parent gene activity Neomorph Novel function, comparing with the initial, new property Antimorph Opposing, antagonizing, or interfering gene activity Isomorph Identical expression with original (parent) allele, mostly resulting from silent point mutations