BCH 313: 2ND PART

BIOSYNTHESIS OF NUCLEOTIDE COENZYMES

==> Nicotinamide Coenzymes

The nicotinamide moiety of the nicotinamide coenzymes (NAD and NADP) is
derived, in humans, from dietary nicotinamide, nicotinic acid, or the essential
amino acid tryptophan. Nicotinate phosphoribosyltransferase which occurs in
most mammalian tissues, catalyzes the formation of nicotinate mononucleotide
from nicotinate and PRPP. This intermediate may also be synthesized from
quinolinate, a degradation product of tryptophan, in a reaction mediated by
quinolinate phosphoribosyltransferase, which occurs mainly in liver and kidney.
Nicotinate mononucleotide is joined via a pyrophosphate linkage to an ATP-
derived AMP residue by NAD+ pyrophosphorylase to yield nicotinate adenine
dinucleotide. Finally, NAD+ synthetase converts this intermediate to NAD+ by a
transamidation reaction in which glutamine is the NH 2 donor.

NAD+ may also be synthesized from nicotinamide. This vitamin is converted to

nicotinamide mononucleotide (NMN) by nicotinamide
phosphoribosyltransferase, a widely occurring enzyme distinct from nicotinate
phosphoribosyltransferase. However, NAD+ is synthesized from NMN and ATP by
NAD pyrophosphorylase, the same enzyme NADP+ that is synthesizes formed via
nicotinate the ATP-dependent adenine dinucleotide. NADP+ is formed via the
ATP-dependent phosphorylation of the NAD+ adenosine residue’s C2’ OH group
by kinase.

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Pathway for the biosynthesis of NAD+ and NADP+

==> Flavin Coenzymes

FAD is synthesized from riboflavin in a two-reaction pathway. First, the 5’-OH

group of riboflavin’s ribityl side chain is phosphorylated by flavokinase, yielding

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flavin mononucleotide (FMN; not a true nucleotide since its ribityl residue is not
a true sugar). FAD may then be formed by the coupling of FMN and ATP-derived
AMP in a pyrophosphate linkage in a reaction catalyzed by FAD
pyrophosphorylase.

Biostnthesis of FMN and FAD from the precursor riboflavin

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==> Coenzyme A
Coenzyme A is synthesized in mammalian cells according to the pathway
diagrammed below. Pantothenate, an essential vitamin, is phosphorylated by
pantothenate kinase and then coupled to cysteine, the future business end of
CoA, by phosphopantothenoylcysteine synthetase. After decarboxylation by
phosphopantothenoylcysteine decarboxylase, the resulting 4’-
phosphopantethiene is coupled to AMP in a pyrophosphate linkage by
dephosphoCoA pyrophosphorylase and then phosphorylated at its adenosine 3’
OH group by dephospho-CoA kinase to form CoA. The latter two enzymatic
activities occur on a single protein.

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 Biosynthesis of Coenzyme A from pantothenate

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