Principles of Biochemistry 22 |Nucleic acids| Class Notes |HarvardX

Quick review

• Building blocks of nucleic acids
• Energy currency in cells (ATP)
• Precursors of universal electron acceptors
• Signaling molecules

RAN: Ribose; DNA: Deoxyribose
Purines: A (Adenine), G (Guanine)
pyrimidine: T (Thymine), C (Cytosine), U (Uracil)

Nucleosides:

• pentos + purine/pyrimidine
• nucleic acid without a phosphate group
  e.g. Adenosine

Nucleotides:

• petos + purine/pyrimidine + one or more phosphates
• Nucleic acid with three phosphates group
  e.g. ATP

DNA/RNA:

• polymerized Nucleotides are linked by a phosphodiester linkage
• Ribonucleotide: RNA
• Dexoyribonucleotide: DNA

Nucleotides Biosynthesis

PRPP: phosphoribosyl pyrophosphate
PRPP + base $\to$ NMP + PP_i

novo pathway:
PRPP + amino acids + HCO₃^- + folate + … $\to$ nucleotide

Glucose-6-P $\overset{Pentose\ phosphate\ pathway}{\to}$ Ribose-5-P $\to$ PRPP

Another contribution of nucleotides
Coenzyme A; cAMP

Novo nucleotide biosynthesis

Inositol monophosphate (IMP) $\to$ AMP/GMP
PRPP $\to$ IMP has 11 steps

1. carbonyl activation
   $Glycine + ATP \to Glycine-P + ADP $
   The carbonyl oxygen of glycine is activated by phosphorylation.

2. Displacement by amine
   $Glycine-P + NH_ 2 -R \to Glycine-NH-R$ R is nucleotide
   …

Purine Biosynthesis:

• By Biochemistry Den (Recommended)
• By Hidaya Aliouche, B.Sc.
• by Sagar Aryal

IMP to AMP/GMP

Regulation of the synthesis

Biosynthesis of pyrimidine

$UMP \to UTP \to CTP$

Formation of the pyrimidine-ring:

• $Carbamoyl-P + Aspartate \overset{ATCase}{\longrightarrow} Carbamoyl aspartate$
• $Carbamoyl aspartate \overset{Dihydroorotase}{\longrightarrow} Dihydroorotate$
• $Dihydroorotate + NAD^ +\overset{Dihydroorotate\ Dihydroorotase}{\longrightarrow} Orotate + NADH + H^ +$

Pyrimidine assemble

• $Orotate + PRPP \to UMP + PP_ i + CO_ 2$
• $UMP + 2ATP \to UTP + 2ADP$
• $UTP + ATP + Gln \to CTP + ADP + P_ i + Glu$

NDP to dNDP

Cancer Treatment

The cancer cell is more sensitive than normal cells to inhibitors of nucleotide biosynthesis

• $dUMP \overset{Thymidylate\ synthase}{\longrightarrow} dTMP$

Folate cycle

Catabolism

Pyrimidine catabolism

$Uridine + Pi \underset{phophorylase}{\overset{Pyrimidine-}{\longleftrightarrow}} Ribose-1-phosphate + Uracil$
$Uracil + NADPH \to Dihydrouracil + NADP^ +$
$Dihydrouracil \overset{Ring cleavage}{\longrightarrow} \beta-alanine + CO_ 2 + NH_ 4^ +$

Adenosine degradation

$Adenosine \ monophosphate (AMP) + H_ 2O \to P_ i + Adenosine$
$Adenosine + H_ 2O \to Inosine + NH_ 3$
$Inosine + H_ 2O \to Ribose + Hypoxanthine$
$Hypoxanthine + O_ 2 + H_ 2O \to Xanthine+ H_ 2O_ 2$

Guanosine degradation

$GMP + P_ i \to Guanosine + H_ 2O$
$Guanosine + H_ 2O \to Ribose + Guanine$
$Guanine + H_ 2O \to Xanthine + NH_ 3$
$Xanthine \overset{Xanthine \ oxidase}{\longrightarrow} Uric \ acid$

Accumulation of Uric acid in blood could cause gout.

treatment

• Reduce the formation of uric acid
  Hypoxanthine and Allopurinal could serve as potent xanthine oxidase inhibitors. By restricted the production of the uric acid, the xanthine remained. But it is more soluble and easy to be cleaned.
• Uric acid degradation
  $Uric acid \overset{Urate oxidase}{\longrightarrow} Allantoin$

Pyrimidine/Purine salvage

Pyrimidine

$Uracil \longleftrightarrow Ribose-1-P$
$Ribose-1-P \overset{Pyrimidine \ phosphorylase}{\longleftrightarrow} Uridine + P_ i$

Purine

$Adenine + PRPP \overset{APRT}{\longrightarrow} Adenosine \ monophosphate$
APRT: adenine phosphoribosyltransferase.
$Guanine + PRPP \overset{HPRT}{\longrightarrow} Guanine \ monophosphate$
HPRT: hypoxanthine guanine phosphoribosyltransferase.

Lesch-Nyhan disease

Genetic deficiency in HPRT

X-linked (Uncommon in females)

It causes Hyperuricemia, Severn neurological symptoms
Allopurinol treats hyperuricemia, but no neurological symptoms.

digraph F { rankdir = LR; "node1" [ label = "<f1> |<f2> IMP|<f3> " shape = "record" color = white fontcolor = "red" fontsize = 20 ]; "node2" [ label = "<f1> Adenylosuccinate| <f2>|<f3> XMP" shape = "record" color = white fontcolor = "red" fontsize = 20 ]; "node3" [ label = "<f1> AMP| <f2>|<f3> GMP" shape = "record" color = white fontcolor = "red" fontsize = 20 ]; node1:f2 -> node2:f1 -> node3:f1 [ style = "bold"] node1:f2 -> node2:f3 -> node3:f3 [ style = "bold"] Asp -> node2:f1 [color = "red"] node3:f1 -> Fumarate [color = "red"] GTP -> node2:f1 -> "GDP+Pᵢ" [color = "green"] "H₂O" -> node2:f3 "NAD⁺" -> node2:f3 Gln -> node3:f3 -> Glu [color = "red"] ATP -> node3:f3 -> "AMP + PPᵢ" [color = "green"] }digraph { node [shape = none] inter1 [ label = "", width=0, height =0] En1 [label = "PRPP\nsynthase", fontcolor="cyan"] En2 [label = "Gln-PRPP\namidotransferase", fontcolor="cyan"] En3 [label = "Adenylosuccinate\nsynthase", fontcolor="cyan"] En4 [label = "IMP\ndehydrogenase", fontcolor="cyan"] En5 [label = "XMP-glutamine\namidotransferase", fontcolor="cyan"] subgraph{ node [fontcolor = "crimson"] AGI [label ="AMP\nGMP\nIMP" ] AMP2 [label = "AMP"] GMP2 [label = "GMP"] } subgraph{ node [fontcolor = "green"] ATP; GTP } "Ribose-5-P" -> En1 -> PRPP -> En2 -> "5-P-ribosylamine" -> IMP -> En3 -> Adenylosuccinate -> inter1 -> AMP IMP -> En4 -> XMP -> En5 -> GMP AGI -> En1 [arrowhead = "tee", color = "crimson"] AGI -> En2 [arrowhead = "tee", color = "crimson"] AMP2 -> En3 [arrowhead = "tee", color = "crimson"] GMP2 -> En4 [arrowhead = "tee", color = "crimson"] GTP -> En3 [color = "green"] ATP -> En5 [color = "green"] }digraph{ subgraph{ node [shape = ellipse, fontcolor ="brown", color = grey, style = "filled"] TS [label = "thymidylate\nsynthase"] DR [label = "dihydrofolate\nreductase"] SHT [label = "serine\nhydroxymethyl-\ntransferase"] } subgraph main{ node [shape = none] "N5,N10-Methylene\nTHF" -> TS -> "7,8-dihydrofolate" -> DR -> THF -> SHT -> "N5,N10-Methylene\nTHF" [style = "bold"] } NADPH -> DR -> "NADP+" [color = red] serine -> SHT -> Glycine [color = red] subgraph cluster_0{ label = "Cancer Drag" node [shape=box, color = red, style = "filled"] edge [arrowhead="tee", color = red] FD [label = "FdUMP"] ME [label = "Methotrexate"] } FD -> TS [arrowhead="tee", color = red] ME -> DR [arrowhead="tee", color = red] }