L19 haem, purine and pyrimidine metabolism

Question 1

Answer 1

Question 2

Nucleoside, Nucleotide vs. Deoxynucleotide

Answer 2

Question 3

Purine Metabolism. De-Novo Synthesis vs. Salvage Pathway vs. Degradation

Answer 3

De novo synthesis pathway

• N atoms from amino acids and C atoms from CO2and formate(HCOO-)
• 7ATP per AMP/GMP formed –DNA replication is energetically expensive

Salvage pathway

•nucleotides are degraded and free purines recycled back into nucleotides

Degradation

•AMP and GMP converted to uric acid and excreted

Question 4

How are Purines Synthesised?

Answer 4

Purines are synthesised as nucleotides, not as free purines

Question 5

Where does Ribose-5 Phosphate from the first step of De Novo Purine Synthesis originate?

Answer 5

Pentose Phosphate Pathway

Question 6

What is the significant of the synthesis of PRPP (phosphoribosyl pyrophosphate)?

Answer 6

It is a rate limiting step in purine synthesis

Also an important intermediate in pyrimidine synthesis

Question 7

In the first stage of De NOvo Purine Synthesis Ribose 5 Phsophate is converted to ____________

Answer 7

IMP (Inosine Monophosphate)

Question 8

The Folate Cycle

What is the main function of Tetrahydrofolate (TH4)?

What enzyme is required to regenerate TH4?

What class of drugs targets this enzyme?

Answer 8

The Folate Cycle

Tetrahydrofolate (TH4) cycles between a number of forms–it’s main function is as a donor of 1C units in the de novo synthesis of purines, thymidylate (pyrimidine) and certain amino acids (glycine, methionine)

In purine synthesis an enzyme called dihydrofolate (DHFR) is required to regenerate TH4

Antifolates are a class of drugs that inhibits DHFR

• some antifolates inhibit several THF requiring pathways (purine and pyrimidine synthesis)
• Target actively dividing cells (antineoplastic)

Question 9

What is the significance of IMP in De Novo Synthesis of Purines?

Answer 9

IMP is a branch point in purine synthesis, broken down into AMP and GMP

Question 10

What helps regulates De Novo Purine Synthesis?

Answer 10

• Classic feedback inhibition of first PRPP synthetase(1) and glutamine PRPP amidotenasferase(2) enzymes by the end products
• Balanced production of AMP and GMP by virtue of the cross regulation of one by the product of the other
  • ATP hydrolysis required for GMP synthesis
  • GTP hydrolysis required for AMP synthesis

GTP abundant, AMP production favoured and vice versa

Question 11

What enzyme is required to convert AMP to Xanthine as part of purine degradation?

What are the consequences of its absence?

Answer 11

Adenosine Deaminase (ADA) is required to convert AMP to xanthine

ADA Deficiency or ADA Severe Combined Immunodefficiency (ADA SCID) is a rare purine metabolic disorder that primarily affects lymphocyte development leading to an underdeveloped thymus gland and severely compromised immune system

ADA is treated with donor bone marrow transplant, enzyme replacement therapy, gene therapy

Question 12

As part of Purine degredation Xanthine is converted to uric acid by ___________. Uric acid has poor solubility in H₂O and as such is excreted in urine as sodium urate.

Answer 12

As part of Purine degredation Xanthine is converted to uric acid by xanthine oxidase. Uric acid has poor solubility in H₂O and as such is excreted in urine as sodium urate.

Question 13

Overproduction and/or underexcretionof uric acid leading to formation of sodium urate crystals in joints and tissues.

What is this condition known as and how is it treated?

Answer 13

Gout / Hyperuricemia

Xanthine oxidase inhibitors (allopurinol) can be used to treat gout

Question 14

Purine Salvage Pathway

• nucleotides converted to bases by successive removal of phosphate and ribose
• free purine bases can be degraded to _________ or salvaged by conversion to their corresponding nucleotides by _______________

Answer 14

Purine Salvage Pathway

• nucleotides converted to bases by successive removal of phosphate and ribose
• free purine bases can be degraded to uric acid** or salvaged by conversion to their corresponding nucleotides by **phosphoribosylation

Question 15

What Syndrome is caused by a deficiency of HGPRTase (enzyme of purine salvage pathway)?

What are its Symptoms?

Answer 15

Lesh Nyhan Syndrome

• X linked disorder
• hyperuricemicstate
• increased oxidation/degradation of purines to uric acid
• severe gout
• Neurologic disability and behavioural problems
  
  • dystonia, delayed development, spasticity
  • cognitive impairment and aggressive and impulsive behavior
  • predilection to self mutilation (lip, tongue and finger biting, head banging)

Question 16

Carbamoyl phosphate involved in De Novo Pyrimmidine Biosynthesis is the same compound as in ________

The enzyme carbamoyl phosphate synthetase II is a different _______ of urea cycle enzyme

Answer 16

Carbamoyl phosphate involved in De Novo Pyrimmidine Biosynthesis is the same compound as in urea cycle

The enzyme carbamoyl phosphate synthetase II is a different isoform of urea cycle enzyme

Question 17

During Pyrimiidine Degredation _________ remose the phosphate and ________ removes the sugar

Answer 17

During Pyrimiidine Degredation Uridine Kinase** remose the phosphate and **Uridine Phosphorylase removes the sugar

Question 18

General Scheme for Synthesis of Deoxyribonucleotides

Answer 18

Question 19

Deoxyribonucleotidesare formed from ribonucleotides by the action of what enzyme?

Answer 19

Ribonucleotide Reductase

Question 20

Thymidylate (dTMP) is a key metabolite required for the accurate replication of DNA genomes in all cellular organisms. De novo synthesis of dTMP requires _________ that methylates dUMP with ______ as a cofactor

Answer 20

Thymidylate (dTMP) is a key metabolite required for the accurate replication of DNA genomes in all cellular organisms. De novo synthesis of dTMP requires Thymidylate Synthase** that methylates dUMP using **THF as a cofactor

Question 21

__________ are tetrapyrrole structures

Answer 21

Porphyrins are tetrapyrrole structures

Question 22

What does the conjugated planar ring structure of Porphyrins facilitate?

Answer 22

Electron Transfer

Question 23

Polyphorins contain a divalent metal ion co-ordinated between the N atoms the 4 pyrrole rings

• iron (__________)
• magnesium (__________)
• cobalt (_____________)

Answer 23

Polyphorings contain a divalent metal ion co-ordinated between the N atoms the 4 pyrrole rings

• iron (haem)
• magnesium (chlorophyll)
• cobalt (cobalamin vitamin B12)

Question 24

Haem synthesis occurs in ______ and ______ cells

Within these cells it begins in the _________ before traveling to ________ and ending back in ___________

Answer 24

Haem synthesis occurs in Bone Marrow** and **Liver cells

Within these cells it begins in Mitochondria** before traveling to the **Cytosol** and ending back in **Mitochondria

Question 25

Known as _________, disorders of porphyrin metabolism is characterised by ___________ of haem and/or its precursors and can arise from one of two sources:

Answer 25

Known as Porphyrias,** disorders of porphyrin metabolism characterised by **overproduction of haem and/or its precursors

• inherited(genetic disorders of porphyrinsynthesis)
• acquired(heavy metal poisoning)

Question 26

Classification and clinical manifestations of Hepatic** vs. **Cutaneous Porphyria:

Answer 26

Hepatic (acute) –mainly affect nervous system

• severe abdominal pain
• acute neuropathy
• muscle weakness
• seizures
• psychosis (hallucinations, anxiety, paranoia)

Cutaneous (erythropoietic) –mainly affect skin

• no abdominal pain
• photosensitivity (skin blistering and necrosis)
• hypertrichosis

Question 27

What disease is beleived to have lead to classification of people as Vampires?

Answer 27

Porphyrias

• Excretion of uroporphyrinogen I coloursthe urine red (vampires excrete blood)
• Some afflicted persons grow excessive hair (hypertrichosis –werewolves )
• Photosensitivity (aversion to daylight
• Anemia (pallor)
• Fresh blood may have been a good source of haem(blood craving

Question 28

What dieases is believed to have afflicted King George and Vincent Van Gogh?

Answer 28

Porphyria

Question 29

What condition can lead toxivity mimic the symptoms of?

How come?

Answer 29

Porphyria

• activity of Porphobilinogen Synthaseis Zn²⁺ dependent
• lead displaces Zn^<u>2+</u> from porphobilinogensynthase
• enzyme activity reduced, accumulation of ALA
• ALA believed to cause neurological effects of lead poisoning

Question 30

Where is Hemoglobin from aging red blood cells broken down?

What is involved in this process?

Answer 30

Reticuloendothelial system (macrophages) in spleen & liver

• Heme is degraded to biliverdin by the enzyme hemeoxygenase(HO)
• Biliverdin (a hydrophilic compound) is reduced by biliverdin reductase into the hydrophobic compound bilirubin
• Transported to liver as a complex with serum albumin and taken up by liver in a carrier mediated process

Question 31

What causes Hyperbilirubinemia of skin, eyes and other tissues?

Answer 31

Also known as Jaundice, accumulation of bilirubin from Haem degredation imparts yellowish colour to skin, eyes

Can be attributed to delay in bilibun metabolism, liver dysfunction or increase hemolysis. High levels of Bilrubin can be neurrotoxic causing seirusres and irreversible damage

Question 32

Answer 32