DNA and Chromosomes

Question 1

What is DNA’s structure and what proteins are it bound around?

Answer 1

DNA is negatively charged and tightly wound round Histones.
Histones have 8 subunits and a H1 linker.
It is condensed into chromatin in the cells.
Barr bodies are condences inactive X chomosomes

Question 2

Describe Heterochromatin and Euchromatin

Answer 2

Heterochromatin - highly condensed and not mitotically active

Euchromatin - Less condensed and is transcriptionally active.

Question 3

Methylation and acetylation of DNA and histones

Answer 3

Template DNA is methylated at cystine and adenine to allow mismatch repair enzymes to recognise the old and new DNA.

DNA methylation at CpG islands ceases DNA replication.

Methylation of Histones - reversible repression of DNA replication

Acetylation of Histones - relaxes DNA coiling making it available for replication.

Question 4

Describe the different nucleotides of DNA?
Purines
Pyramidines

Answer 4

Ribose nucleotides are made first and then converted to deoxy forms by ribonucleotide reductase.

Nucleosides are base + (deoxy)ribose
Nuclotides are base + sugar + phosphate (phosphodiester bond 3’ –>5’)

Purines

• Adenosine, Guanine,
• two rings, Glycine, Asparatate and Glutamine needed for synthesis.

Pyramindines

• Cytosine, Thymine, Uracil (RNA)
• require carbonyl phosphate and Aspartate

Question 5

Describe the Synthesis of Purines.

Answer 5

• start with sugar and phosphate (PhosphoRibosyl PyroPhosphate)
• Add a base - This makes Inosine MP, this is then converted to either AMP or GMP.

In this process PRPP –> IMP is inhibited by 6-mercaptopurine (and azathioprine)

IMP –> GMP is inhibited by Mycophenolate and ribavirin as these both inhibit IMP dehydrogenase.

Question 6

Describe the Synthesis of Pyramidines

Answer 6

Glutamine and CO2 converted to Carbamoyl phosphate by Carbomyl phosphate synthetase II.

Carbomyl phosphate is combined with Aspartate to form Orotic Acid. (this step is inhibited by leflunomide)

Orotic acid is combined with PRPP to form UMP.

UMP is converted to UDP which can be converted to CTP.

UDP can also be converted to deoxyUDP by ribonucleotide reductase (inhibited by hydroxyurea)

deoxyUDP is combined with methylene TetraHydroFolate converted to dTMP and dihydrofolate via Thymidylate synthase (this is inhibited by 5-fluorouracil)

THF is made via DHF being reduced by dihydrofolate reducatase (this step is inhibited by Methotrexate, Trimethoprim and Pyrimethamine in humans, bacteria and protazoa respectfully)

Question 7

Purine salvage deficiencies:

Adenosine deaminase deficiency

Answer 7

ADA is involved in converting adenosine to Inosine.
its deficiency leads to excess ATP and dATP leading to inhibition of ribonuclease reducatase –> this prevents DNA synthesis and leads to decreased lymphocyte count.

This is a major cause of Autosomal recessive Severe Combined Immunodeficiency. (SCID)

Question 8

Describe Lesch-Nyhan Syndrome

Answer 8

Absent Hypoxanthine guanine phosphoribosyltransferase (HGPRT) which is important in converting hypoxanthine into IMP and guanine to GMP.

leads to excess uric acid and de novo purine synthesis

X-linked Recessive disorder.

On examination - Learning disability, Self harm, aggressive, Hyperuracemia –> gout, dystonia

Hyperuricemia , Gout, Pissed off(aggressive) Retardation, dysTonia (HGPRT)

Question 9

Treatment in Lesch-Nyhan Syndrome

Answer 9

Allopurinol or febuxostat as this inhibitors Xanthine Oxidase preventing hyperuracemia.