0 Posted 2021-06-18Updated 2024-01-11Notes / Class / Biochemistry5 minutes read (About 816 words)

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

purine synthesis

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

carbonyl activation
$Glycine + ATP \to Glycine-P + ADP $
The carbonyl oxygen of glycine is activated by phosphorylation.
Displacement by amine
$Glycine-P + NH_ 2 -R \to Glycine-NH-R$ R is nucleotide
…

Purine Biosynthesis:

IMP to AMP/GMP

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"]

}

Regulation of the synthesis

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”]
}

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

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]
}

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.