Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.2.1.13 (
glyceraldehyde-3-phosphate dehydrogenase
)
6,511
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The adoption of Warburg metabolism is critical for the activation of macrophages in response to lipopolysaccharide. Macrophages stimulated with lipopolysaccharide increase their expression of
nicotinamide phosphoribosyltransferase
(
NAMPT
), a key enzyme in NAD
+
salvage, and loss of
NAMPT
activity alters their inflammatory potential. However, the events that lead to the cells' becoming dependent on NAD
+
salvage remain poorly defined. We found that depletion of NAD
+
and increased expression of
NAMPT
occurred rapidly after inflammatory activation and coincided with DNA damage caused by reactive oxygen species (ROS). ROS produced by complex III of the mitochondrial electron-transport chain were required for macrophage activation. DNA damage was associated with activation of poly(ADP-ribose) polymerase, which led to consumption of NAD
+
. In this setting, increased
NAMPT
expression allowed the maintenance of NAD
+
pools sufficient for
glyceraldehyde-3-phosphate dehydrogenase
activity and Warburg metabolism. Our findings provide an integrated explanation for the dependence of inflammatory macrophages on the NAD
+
salvage pathway.
...
PMID:Inflammatory macrophage dependence on NAD
+
salvage is a consequence of reactive oxygen species-mediated DNA damage. 3085 21
All cells require sustained intracellular energy flux, which is driven by redox chemistry at the subcellular level. NAD
+
, its phosphorylated variant NAD(P)
+
, and its reduced forms NAD(P)/NAD(P)H are all redox cofactors with key roles in energy metabolism and are substrates for several NAD-consuming enzymes (
e.g.
poly(ADP-ribose) polymerases, sirtuins, and others). The nicotinamide salvage pathway, constituted by nicotinamide mononucleotide adenylyltransferase (NMNAT) and
nicotinamide phosphoribosyltransferase
(
NAMPT
), mainly replenishes NAD
+
in eukaryotes. However, unlike NMNAT1,
NAMPT
is not known to be a nuclear protein, prompting the question of how the nuclear NAD
+
pool is maintained and how it is replenished upon NAD
+
consumption. In the present work, using human and murine cells; immunoprecipitation, pulldown, and surface plasmon resonance assays; and immunofluorescence, small-angle X-ray scattering, and MS-based analyses, we report that
GAPDH
and
NAMPT
form a stable complex that is essential for nuclear translocation of
NAMPT
. This translocation furnishes NMN to replenish NAD
+
to compensate for the activation of NAD-consuming enzymes by stressful stimuli induced by exposure to H
2
O
2
or
S
-nitrosoglutathione and DNA damage inducers. These results indicate that by forming a complex with
GAPDH
,
NAMPT
can translocate to the nucleus and thereby sustain the stress-induced NMN/NAD
+
salvage pathway.
...
PMID:A nicotinamide phosphoribosyltransferase-GAPDH interaction sustains the stress-induced NMN/NAD
+
salvage pathway in the nucleus. 3198 40
