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:2.3.3.1 (
citrate synthase
)
4,488
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The tricarboxylic acid (TCA) cycle (or citric acid cycle) is responsible for the complete oxidation of acetyl-CoA and formation of intermediates required for ATP production and other anabolic pathways, such as amino acid synthesis. Here, we uncovered an additional mechanism that may help explain the essential role of the TCA cycle in the early embryogenesis of
Caenorhabditis elegans.
We found that knockdown of
citrate synthase
(
cts-1
), the initial and rate-limiting enzyme of the TCA cycle, results in early embryonic arrest, but that this phenotype is not because of ATP and amino acid depletions. As a possible alternative mechanism explaining this developmental deficiency, we observed that
cts-1
RNAi embryos had elevated levels of intracellular acetyl-CoA, the starting metabolite of the TCA cycle. Of note, we further discovered that these embryos exhibit hyperacetylation of mitochondrial proteins. We found that supplementation with acetylase-inhibiting polyamines, including spermidine and putrescine, counteracted the protein hyperacetylation and developmental arrest in the
cts-1
RNAi embryos. Contrary to the hypothesis that spermidine acts as an acetyl sink for elevated acetyl-CoA, the levels of three forms of acetylspermidine,
N
1
-acetylspermidine,
N
8
-acetylspermidine, and
N
1
,
N
8
-diacetylspermidine, were not significantly increased in embryos treated with exogenous spermidine. Instead, we demonstrated that the mitochondrial deacetylase
sirtuin 4
(encoded by the
sir-2.2
gene) is required for spermidine's suppression of protein hyperacetylation and developmental arrest in the
cts-1
RNAi embryos. Taken together, these results suggest the possibility that during early embryogenesis, acetyl-CoA consumption by the TCA cycle in
C. elegans
prevents protein hyperacetylation and thereby protects mitochondrial function.
...
PMID:Tricarboxylic acid cycle activity suppresses acetylation of mitochondrial proteins during early embryonic development in
Caenorhabditis elegans
. 3060 36
