Role of NAD in ADP-ribosylation

NAD functions in ADP-ribosylation, a reversible
post-translational modifi cation of proteins in which
the ADP-ribose moiety of NAD is transferred to
acceptor proteins, thereby altering their function.
ADP-ribosylation reactions are classifi ed into two
major groups: mono-ADP-ribosylation and poly-
ADP-ribosylation.
Mono-ADP-ribosylation by bacterial toxins
The transfer of ADP-ribose to the acceptor protein
(Fig. 13.5) is catalysed by ADP-ribosyltransferases,
which are found in the cytosol, plasma membrane and
nuclear envelope of eukaryotic cells. The ADP-ribose
reacts with specifi c amino acid residues on the acceptor
protein to form N-glycosides. Certain bacterial
toxins also possess ADP-ribosyltransferase activity
(Ueda & Hayaishi, 1985) and, since more is known
about them than eukaryotic ADP-ribosyltransferases,
they will be selected as examples.
Two bacterial exotoxins, diphtheria toxin and
Pseudomonas aeruginosa exotoxin A, prevent protein
synthesis in bacterially infected eukaryotic cells by
inactivating elongation factor 2, a protein required
for polypeptide chain elongation. The uncontrolled
action of these exotoxins results in death of the host
cells. A mammalian cellular ADP-ribosyltransferase
also inactivates elongation factor 2 (Iglewski, 1994),
but this is a controlled action required for normal
protein synthesis.
Cholera toxin and Escherichia coli heat-labile enterotoxin
ADP-ribosylate the α subunit of the stimulatory
G protein, Gs, which relays the signal from a
hormone-activated cell surface receptor to an intracellular
effector, in this case adenylyl cyclase (see Section
3.7.5). Cholera toxin-catalysed ADP-ribosylation
inhibits the intrinsic GTPase activity of Gsα, resulting
in stabilization of an active GTP-bound subunit and
persistent activation of adenylyl cyclase. ADP-ribosyltransferase
activity of cholera toxin is enhanced
by ADP-ribosylation factor (ARF), a GTP-dependent
eukaryotic protein that functions in intracellular vesicular
transport (Moss & Vaughn, 1995).
Pertussis toxin ADP-ribosylates the α subunit of
the inhibitory G protein, Gi. The modifi ed G protein
uncouples from the receptor, thereby maintaining
the protein as its inactive heterotrimer. Because this
inhibitory G protein is inactivated, inhibition of
adenylyl cyclase is removed and the result is increased
cyclase activity.