Nucleic Acids Structer and FunctionNucleic Acids Structer and Function

Nucleic acids structer and function Biomedical Importance

This polymeric molecule, deoxyribonucleic acid (DNA), is the chemical basis of heredity and is organized into genes, the fundamental units of genetic information.

The basic information pathway ; DNA directs the synthesis of RNA, which in turn directs protein synthesis — has been elucidated. = Central Dogma

Genes do not function autonomously; their replication and function are controlled by various gene products, often in collaboration with components of various signal transduction pathways.

Knowledge of the structure and function of nucleic acids is essential in understanding genetics and many aspects of pathophysiology as well as the genetic basis of disease.

DNA

DNA is a linear polymer of deoxyribonucleotides in which the sequence of purine and pyrimidine bases encodes cellular RNA and protein molecules.

DNA is highly organized into chromosomes, structures that allow the DNA to be packaged tightly for storage in the nucleus of the cell.

DNA The information contained in the DNA is represented by the

sequence of the bases of the polymer, the purines adenine (A) and guanine (G) and the pyrimidines cytosine (C) and thymine (T).

The deoxyribonucleotides in the DNA polymer are connected by phosphodiester bonds between the 5′-phosphate group attached to one deoxyribose sugar and the 3′-hydroxyl group of the next sugar.

This sugar-phosphate backbone is located on the outside of the structure.

DNADNA is double-stranded.1. The two strands run in reverse

polarity or antiparallel to each other.

2. The strands are held together by hydrogen bonding between the bases, with a purine always bonded with a pyrimidine in specific base pairs.

a. Base pairs have a preferred structural complementarity.

b. A pairs with T via two hydrogen bonds.

c. G pairs with C via three hydrogen bonds.

Bounds

Hidrogen bond ; B-BPhosphodiester bonds ; P-PBeta , N - glycosidic bonds , B-S

Specific Enzymes Digest Nucleic Acids

Deoxyribonucleases.

Ribonucleases.

Endonucleases.

Exonucleases.

Phospodiesterases

Nücleotidase

Phosphoylases

DNA Double-stranded DNA exists in at

least six forms (A–E and Z).

The B form is usually found under physiologic conditions (low salt, high degree of hydration).

A single turn of B-DNA about the axis of the molecule contains ten base pairs. The distance spanned by one turn of B-DNA is 3.4 nm (34 Å).

The width (helical diameter) of the double helix in B-DNA is 2 nm

(20 Å).

G–C bonds are much more resistant to denaturation, or "melting," than A–T-rich regions

DNAIn B DNA, the form

that occurs most commonly under physiologic conditions, the helix has major and minor grooves, which provide access for protein binding to the DNA.

DNACooperation between the many

hydrogen bonds and base-stacking interactions makes DNA very stable to chemical treatments.

a. Increased heat, decreased salt concentration, or extremes of pH can force the DNA duplex to melt open (or “unzip”) by disrupting the hydrogen bonds = denaturation.

b. its percentage of G and C bases, which provide a stronger base-pair interaction than A and T pairs.

Compacting of the DNA for storage in the limited space available in the cell’s nucleus is accomplished by binding of proteins

1. A family of small, basic proteins called histones is responsible for major interactions with DNA in the formation of nucleosomes.

a. Prokaryotic histones are of five types: H1, H2A, H2B, H3 and H4; vertebrates also have histone H5.

b. Binding of the positively charged histones to DNA neutralizes negative charges of the phosphate groups along the DNA backbone, which allows the DNA to bend much more easily than naked DNA.

DNA

DNA Two molecules each of the similarly

sized histones H2A, H2B, H3, and H4 bind together in an octamer that forms the core of a nucleosome.

a. DNA wraps around each nucleosome core 1.75 times, so that the nucleosomes form at uniform intervals along the DNA.

b. Approximately 146 base pairs of DNA are involved in forming each nucleosome,with about 30-base-pair linker regions between them.

c. Various types of histone H1 (or H5) bind loosely to the linker regions to help organize the nucleosomes into higher-order structures.

RNARNA molecules operate at critical points in many of the

processes that involve expression of the information represented in the DNA.

1. Transcription is the process by which RNA copies of the genes are synthesized as the first step leading to gene expression.

2. Messenger RNAs (mRNAs) carry copies of the genes that can be translated into proteins

3. Other specialized RNAs, ribosomal RNA (rRNA), transfer RNAs (tRNAs), and small RNA molecules are not translated into protein but have central roles in gene expression and protein synthesis.

4. In eukaryotes, mRNAs are initially transcribed as heterogeneous nuclear RNA( hnmRNA) , which still contains intervening sequences of the gene and must undergo processing to attain the final mRNA structure.

RNAAll RNA molecules represent copies of genes on

the cellular DNA, but there are some important differences in structure between DNA and RNA.

The features of RNA structure that distinguish it from DNA follow:

a. Presence of ribose as the sugar in the backbone of RNA rather than 2′-deoxyribose as in DNA.

b. Thymine (T) in DNA is replaced by uracil (U) in RNA.

c. RNA is a single-stranded version of one strand of the DNA sequence, at least as initially synthesized.

d. RNA can form complex, variable secondary structures by internal foldback and intramolecular base pairing between complementary regions of the molecule.

e.Most types of cellular RNA are involved in various steps in protein synthesisor gene expression.

Those cytoplasmic RNA molecules that serve as templates for protein synthesis (ie, that transfer genetic information from DNA to the protein-synthesizing machinery) are designated messenger RNAs, or mRNAs.

Many other cytoplasmic RNA molecules (ribosomal RNAs; rRNAs) have structural roles where in they contribute to the formation and function of ribosomes (the organellar machinery for protein synthesis) or

serve as adapter molecules (transfer RNAs; tRNAs) for the translation of RNA information into specific sequences of polymerized amino acids

In all eukaryotic cells there are small nuclear RNA (snRNA) species that are not directly involved in protein synthesis but play pivotal roles in RNA processing.

Messenger RNA The expression of

genetic information in DNA into the form of an mRNA transcript.

This is subsequently translated by ribosomes into a specific protein molecule.

Messenger RNA The 5' terminal of mRNA is "capped"

by a 7- methylguanosine triphosphate that is linked to an adjacent 2'-O-methyl ribonucleoside at its 5'-hydroxyl through the three phosphates

The cap is involved in the recognition of mRNA by the translation machinery, and it probably also helps stabilize the mRNA by preventing the attack of 5'-exonucleases.

The protein-synthesizing machinery begins translating the mRNA into proteins beginning downstream of the 5' or capped terminal.

Messenger RNAThe other end of most mRNA molecules,

the 3'-hydroxyl terminal, has an attached polymer of adenylate residues 20–250 nucleotides in length.

The specific function of the poly(A) "tail" at the 3'-hydroxyl terminal of mRNAs is not fully understood, but it seems that it maintains the intracellular stability of the specific mRNA by preventing the attack of 3'-exonucleases.

Some mRNAs, including those for some histones, do not contain poly(A).

Both the mRNA "cap" and "poly(A) tail" are added posttranscriptionally by nontemplate-directed enzymes.

Heterogeneous nuclear RNAThese nuclear RNA molecules,

precursors to the mature, fully processed mRNAs, are very heterogeneous in size and are quite large.

hnRNA molecules are processed to generate the mRNA molecules which then enter the cytoplasm to serve as templates for protein synthesis.

Transfer RNA (tRNA)

tRNA molecules vary in length from 74 to 95 nucleotides. The tRNA molecules serve as adapters for the translation of the information in the sequence of nucleotides of the mRNA into specific amino acids.

There are at least 20 species of tRNA molecules in every cell, at least one (and often several) corresponding to each of the 20 amino acids required for protein synthesis.

Transfer RNA

All tRNA molecules contain four main arms. The acceptor arm terminates in the nucleotides CpCpAOH.

These three nucleotides are added posttranscriptionally by a specific nucleotidyl transferase enzyme.

The tRNA-appropriate amino acid is attached, or "charged" onto, the 3'-OH group of the A moiety of the acceptor arm.

The anticodon, T C, and dihydrouracil (D) arms are indicated, as are the positions of the intramolecular hydrogen bonding between these base pairs.

Ribosomal RNA

The function of the ribosome, including its main catalytic activity, depends on

several forms of ribosomal RNA (rRNA).

1. Ribosomes are large nucleoprotein machines composed of large and small

subunits that carry out protein synthesis.

2. Prokaryotic ribosomes contain three rRNAs: 16S rRNA in the small (30S) subunit and 23S and 5S rRNA molecules in the large (50S) subunit.

3. Eukaryotic ribosomes contain four rRNAs analogous to those in prokaryotes:

the 18S rRNA of the small (40S) subunit and the 28S, 5.8S, and 5S of the large (60S) subunit.

snRNAs, a subset of the small RNAs, are snRNAs, a subset of the small RNAs, are significantly involved in significantly involved in mRNA processingmRNA processing and gene regulation.and gene regulation.

Of the several snRNAs, Of the several snRNAs, U1, U2, U4, U5, and U1, U2, U4, U5, and U6U6 are involved in intron removal and the are involved in intron removal and the processing of hnRNA into mRNAprocessing of hnRNA into mRNA

The U7 snRNA is involved in production of the The U7 snRNA is involved in production of the correct 3' ends of histone mRNA—which correct 3' ends of histone mRNA—which lacks a poly(A) tail. lacks a poly(A) tail.

Micro RNAsPlay important roles in gene regulation.

Presently, all known miRNAs and siRNAs cause inhibition of gene expression

miRNAs are typically 21–25 nucleotides in length and are generated by nucleolytic processing of the products of distinct genes/transcription units

Leading via unknown mechanisms to translation arrest.

To date, hundreds of distinct miRNAs have been described in humans.

Both miRNAs and siRNAs represent exciting new potential targets for therapeutic drug development in humans.