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Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle
Across different kingdoms of life, ATP citrate lyase (ACLY, also known as ACL) catalyses the ATP-dependent and coenzyme A (CoA)-dependent conversion of citrate, a metabolic product of the Krebs cycle, to oxaloacetate and the high-energy biosynthetic precursor acetyl-CoA
1
. The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine
2
, and the acetylation of histones and proteins
3
,
4
. In autotrophic prokaryotes, ACLY is a hallmark enzyme of the reverse Krebs cycle (also known as the reductive tricarboxylic acid cycle), which fixates two molecules of carbon dioxide in acetyl-CoA
5
,
6
. In humans, ACLY links carbohydrate and lipid metabolism and is strongly expressed in liver and adipose tissue
1
and in cholinergic neurons
2
,
7
. The structural basis of the function of ACLY remains unknown. Here we report high-resolution crystal structures of bacterial, archaeal and human ACLY, and use distinct substrate-bound states to link the conformational plasticity of ACLY to its multistep catalytic itinerary. Such detailed insights will provide the framework for targeting human ACLY in cancer
8
–
11
and hyperlipidaemia
12
,
13
. Our structural studies also unmask a fundamental evolutionary relationship that links citrate synthase, the first enzyme of the oxidative Krebs cycle, to an ancestral tetrameric citryl-CoA lyase module that operates in the reverse Krebs cycle. This molecular transition marked a key step in the evolution of metabolism on Earth.
Crystal structures of ATP citrate lyase from bacteria, archaea and humans unravel how the enzyme directs the formation of the central metabolite acetyl-CoA, and shed light onto the evolutionary origins of the Krebs cycle.
Journal Article
The Effect of Green Human Resource Management on Environmental Performance in Small Tourism Enterprises: Mediating Role of Pro-Environmental Behaviors
Research on the interrelationship between green human resource management (GHRM), employee pro-environmental behaviors, and environmental performance remains very limited, especially in relation to small tourism enterprises. This research bridges a knowledge gap and examines the direct effect of GHRM on environmental performance in small tourism enterprises and the indirect effect through employee pro-environmental behaviors. For this purpose, a quantitative research approach was adopted using a pre-tested instrument. A questionnaire was handed to employees in small hotels and travel agencies in Greater Cairo, Egypt. The results of structural equation modeling (SEM) showed a positive significant effect of GHRM on both types of pro-environmental behaviors (tasked-related and proactive). However, the results, surprisingly, showed no significant direct effect of GHRM on environmental performance. Notwithstanding, there was an indirect, positive, and significant effect of GHRM on environmental performance through tasked-related and proactive pro-environmental behaviors. This reflects the value and vital role of employee pro-environmental behaviors in the relationship between GHRM and environmental performance in small tourism enterprises. The research provided various implications for tourism scholars and practitioners, especially those related to small tourism enterprises. Research limitations and opportunities for further research are also discussed.
Journal Article
An allosteric mechanism for potent inhibition of human ATP-citrate lyase
ATP-citrate lyase (ACLY) is a central metabolic enzyme and catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA
1
–
5
. The acetyl-CoA product is crucial for the metabolism of fatty acids
6
,
7
, the biosynthesis of cholesterol
8
, and the acetylation and prenylation of proteins
9
,
10
. There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation
2
,
5
,
11
. ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials
4
,
5
. Many inhibitors of ACLY have been reported, but most of them have weak activity
5
. Here we report the development of a series of low nanomolar, small-molecule inhibitors of human ACLY. We have also determined the structure of the full-length human ACLY homo-tetramer in complex with one of these inhibitors (NDI-091143) by cryo-electron microscopy, which reveals an unexpected mechanism of inhibition. The compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding. The observed binding mode is supported by and explains the structure–activity relationships of these compounds. This allosteric site greatly enhances the ‘druggability’ of ACLY and represents an attractive target for the development of new ACLY inhibitors.
The structure of human ATP-citrate lyase, in complex with a newly developed small-molecule inhibitor, shows extensive conformational changes that reveal an allosteric site for the inhibitor to bind and indirectly compete with the citrate substrate.
Journal Article
Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate
Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods
1
, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease
2
–
4
. Fructose intake triggers de novo lipogenesis in the liver
4
–
6
, in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates
7
. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases
8
. However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of
Acly
in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota
9
, and this supplies lipogenic acetyl-CoA independently of ACLY
10
. Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.
A genetic mouse model is used to reveal a two-pronged mechanism of fructose-induced de novo lipogenesis in the liver, in which fructose catabolism in hepatocytes provides a signal to promote lipogenesis, whereas fructose metabolism by the gut microbiota provides acetate as a substrate to feed lipogenesis.
Journal Article
Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol
Short-term studies indicate that bempedoic acid, an ATP citrate lyase inhibitor, reduces LDL cholesterol levels. In a 1-year trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of adverse events than placebo and led to significantly lower LDL cholesterol levels.
Journal Article