Nuleic Acid

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Nucleotide biosynthesis

Dr\ Gamal Alhazmi



P yrimidine nucleotide biosynthesisthrough a de novo pathway

Nucleotides are also produced through a de novo pathway synthesizing new bases.

P yrimidine nucleotide synthesis starts with thesynthesis of carbamoyl phosphate from carbonate. ATP provides the energy needed for the reaction andthe -NH 2 group is from glutamine.

.



As shown in Figure 6.20, orotate is synthesized as a

precursor of pyridine nucleotides before binding to

PRPP by the action of phosphoribosyltransferase as in

the salvage pathway described previously.

Mononucleotides are phosphorylated in two steps to

trinucleotide by nucleotide kinases, consuming ATP,

before being used in R NA synthesis.

The first enzyme of pyridine nucleotide biosynthesis,aspartate transcarbamoylase, is regulated through

feedback inhibition by cytidine trinucleotide, the final

product.



De novo synthesis of purine nucleotidesPurine nucleotides are synthesized in a more complicated

pathway than pyrimidine nucleotides.

Glutamine donates -NH 2 to PRPP before

inosine 5-monophosphate (IMP) is synthesized with the

addition of carbons and nitrogens in the forms of glycine,

methenyl tetrahydrofolate, glutamine, aspartate and

formyl tetrahydrofolate (Figure 6.21).

IMP is converted to adenosine 5-monophosphate (AMP) and

guanosine 50-monophosphate (GMP).



The first enzyme of this pathway, PRPPamidotransferase, is regulated through feedback

inhibition by the final products AMP and GMP. These

are phosphorylated to dinucleotides in reactionscatalyzed by nucleotide kinases that consume A TP.GDP is further phosphorylated to GTP in a similarreaction, and ADP to A TP in the normal A TP

synthesis mechanisms either by substrate-levelphosphorylation or by the membrane-bound A TPase .



TranscriptionTranscription is the process of RNA synthesis from the DNA

template.

Major RNA types include mRNA, rRNA and tRNA with specific

functions in expression of the genetic information. They are all

synthesized in a similar way before being modified to their own

specific forms through post-transcriptional processing.



R NA synthesisRNA is synthesized through transcription, a process as complex

as replication. RNA polymerase (DNA-dependent RNA

polymerase) catalyzes the formation of phosphodiester bonds

between ribonucleotides consuming GTP, CTP, A TP or UTP

depending on the base pairing within DNA.

The synthesis proceeds in the 53 direction as in

Replication.



Certain regions in DNA have a strong affinity for RNA polymerase and are referred to as promoters. RNA

polymerase recognizes and binds the promoter region of

DNA to start RNA synthesis.RNA polymerase consists of five subunits in the ratio of 2

in bacteria. The -factor of the enzyme recognizes the

promoter region of DNA, and the enzyme complex binds to it. At this point, the -factor is separated from the complex and

the core enzyme 2 moves along the DNA synthesizing

RNA according to a base-pairing mechanism.



Multiple -factors are known in bacteria which recognize

different promoter regions. Proteins known as activators and

repressors control the activity of some promoters

(Section 12.1).Transcription is terminated either by an intrinsic input

mechanism involving a specific DNA region known as

atermination site or by an extrinsic input mechanism exerted by a protein -factor.



Translation

Translation is the process in which the genetic information

passed on to mRNA is used to make proteins. As the genetic

information carried by DNA is passed to RNA during

transcription, the information in mRNA is translated into

protein through an amino acid sequence encoded by the

sequence of bases in the mRNA

(Table 6.7). Amino acids are activated before beingpolymerized into peptide.



Amino acid activation

Amino acids are activated to aminoacyl-tRNA consuming A TP:

enzyme : aminoacyl tRNA synthetase

The aminoacyl-tRNA synthetase catalyzing this reaction

recognizes not only amino acids but also tRNA. More than one

tRNA is needed for each amino acid since most of the amino

acids are coded by multiple codons, except methionine and

tryptophan (Table 6.7), and a tRNA is needed for each codon

base pairing with its specific anticodon



S ynthesis of peptide: initiation, elongationand termination

The coding region in mRNA starts with AUG. Peptide synthesis

starts with methionine in eukaryotes and with

N-formylmethionine in bacteria.

AUG (T AC on DNA) is referred to as the initiation codon.

Though peptide synthesis is a continuous process, translation

can be described for convenience as initiation, elongation and

termination steps

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