Low Plasma Citrate Levels and Specific Transcriptional Signatures Associated with Quiescence of CD34+ Progenitors Predict Azacitidine Therapy Failure in MDS/AML Patients

To better understand the molecular basis of resistance to azacitidine (AZA) therapy in myelodysplastic syndromes (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), we performed RNA sequencing on pre-treatment CD34+ hematopoietic stem/progenitor cells (HSPCs) isolated from 25 MDS/AML-MRC patients of the discovery cohort (10 AZA responders (RD), six stable disease, nine progressive disease (PD) during AZA therapy) and from eight controls. Eleven MDS/AML-MRC samples were also available for analysis of selected metabolites, along with 17 additional samples from an independent validation cohort. Except for two patients, the others did not carry isocitrate dehydrogenase (IDH)1/2 mutations. Transcriptional landscapes of the patients’ HSPCs were comparable to those published previously, including decreased signatures of active cell cycling and DNA damage response in PD compared to RD and controls. In addition, PD-derived HSPCs revealed repressed markers of the tricarboxylic acid cycle, with IDH2 among the top 50 downregulated genes in PD compared to RD. Decreased citrate plasma levels, downregulated expression of the (ATP)-citrate lyase and other transcriptional/metabolic networks indicate metabolism-driven histone modifications in PD HSPCs. Observed histone deacetylation is consistent with transcription-nonpermissive chromatin configuration and quiescence of PD HSPCs. This study highlights the complexity of the molecular network underlying response/resistance to hypomethylating agents.

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The reductive tricarboxylic acid cycle of carbon dioxide assimilation: initial studies and purification of ATP-citrate lyase from the green sulfur bacterium Chlorobium tepidum.

Journal of Bacteriology ◽

10.1128/jb.179.15.4859-4867.1997 ◽

1997 ◽

Vol 179 (15) ◽

pp. 4859-4867 ◽

Cited By ~ 45

Author(s):

T M Wahlund ◽

F R Tabita

Keyword(s):

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Chlorobium Tepidum ◽

Green Sulfur Bacterium ◽

Carbon Dioxide Assimilation ◽

Atp Citrate Lyase ◽

Acid Cycle ◽

Citrate Lyase ◽

Green Sulfur ◽

Reductive Tricarboxylic Acid Cycle

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Activity and androgenic control of enzymes associated with the tricarboxylic acid cycle, lipid oxidation and mitochondrial shuttles in the epididymis and epididymal spermatozoa of the rat

Biochemical Journal ◽

10.1042/bj1740741 ◽

1978 ◽

Vol 174 (3) ◽

pp. 741-752 ◽

Cited By ~ 31

Author(s):

D E Brooks

Keyword(s):

Lipid Oxidation ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Active Member ◽

Carnitine Acetyltransferase ◽

Atp Citrate Lyase ◽

Acid Cycle ◽

Citrate Lyase ◽

Epididymal Spermatozoa ◽

Glycerol 3 Phosphate Dehydrogenase

1. Enzyme activities (units/g wet wt.) were determined in the caput and cauda epididymidis and in epididymal spermatozoa of the rat. 2. The activity of most enzymes in the cauda was between 50 and 100% of that in the caput, except that ATP citrate lyase was barely detectable in the cauda. 3. Spermatozoa, unlike epididymal tissue, contained sorbitol dehydrogenase but lacked ATP citrate lyase. NADP+-malate dehydrogenase, mitochondrial glycerol 3-phosphate dehydrogenase, succinate dehydrogenase, carnitine acetyltransferase and citrate synthase were 5 to 400 times as active in spermatozoa as in epididymal tissue. 4. 2-Oxoglutarate dehydrogenase was the least active member of the tricarboxylic acid cycle in all tissues and most closely matched the measured flux through the cycle. 5. The concentrations of hydroxyacyl-CoA dehydrogenase and carnitine palmitoyltransferase were equivalent to the more active enzymes of the tricarboxylic acid cycle, indicating the capacity for extensive lipid oxidation, and the presence of 3-hydroxybutyrate dehydrogenase suggests that these tissues can also oxidize ketone bodies. 6. Transfer of reducing equivalents from cytoplasm to mitochondrion is unlikely to occur by means of the glycerol phosphate cycle because mitochondrial glycerol 3-phosphate dehydrogenase is relatively inactive in epididymal tissue, whereas the cytoplasmic enzyme has little activity in spermatozoa, but transfer may be accomplished by the malate-aspartate shuttle. 7. Transfer of acetyl units from mitochondrion to cytoplasm could be effected by the pyruvate-malate cycle in the caput of androgen-maintained rats, but not in the other tissues because of the low activity of ATP citrate lyase. Acetyl unit transfer could take place via acetylcarnitine, mediated by carnitine acetyltransferase. 8. Castration resulted in a decrease in the concentration of nearly all enzymes, although subsequent administration of testosterone restored concentrations to values similar to those in animals maintained by endogenous androgen. The extent to which enzyme concentration was changed by an alteration in androgen status was highly variable, but was most marked in the case of pyruvate carboxylase.

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Evidence for Autotrophic CO2 Fixation via the Reductive Tricarboxylic Acid Cycle by Members of the ε Subdivision of Proteobacteria

Journal of Bacteriology ◽

10.1128/jb.187.9.3020-3027.2005 ◽

2005 ◽

Vol 187 (9) ◽

pp. 3020-3027 ◽

Cited By ~ 144

Author(s):

Michael Hügler ◽

Carl O. Wirsen ◽

Georg Fuchs ◽

Craig D. Taylor ◽

Stefan M. Sievert

Keyword(s):

Carbon Fixation ◽

Tricarboxylic Acid Cycle ◽

Calvin Cycle ◽

Tricarboxylic Acid ◽

Rrna Gene ◽

Atp Citrate Lyase ◽

Acid Cycle ◽

Key Enzymes ◽

Citrate Lyase ◽

Reductive Tricarboxylic Acid Cycle

ABSTRACT Based on 16S rRNA gene surveys, bacteria of the ε subdivision of proteobacteria have been identified to be important members of microbial communities in a variety of environments, and quite a few have been demonstrated to grow autotrophically. However, no information exists on what pathway of autotrophic carbon fixation these bacteria might use. In this study, Thiomicrospira denitrificans and Candidatus Arcobacter sulfidicus, two chemolithoautotrophic sulfur oxidizers of the ε subdivision of proteobacteria, were examined for activities of the key enzymes of the known autotrophic CO2 fixation pathways. Both organisms contained activities of the key enzymes of the reductive tricarboxylic acid cycle, ATP citrate lyase, 2-oxoglutarate:ferredoxin oxidoreductase, and pyruvate:ferredoxin oxidoreductase. Furthermore, no activities of key enzymes of other CO2 fixation pathways, such as the Calvin cycle, the reductive acetyl coenzyme A pathway, and the 3-hydroxypropionate cycle, could be detected. In addition to the key enzymes, the activities of the other enzymes involved in the reductive tricarboxylic acid cycle could be measured. Sections of the genes encoding the α- and β-subunits of ATP citrate lyase could be amplified from both organisms. These findings represent the first direct evidence for the operation of the reductive tricarboxylic acid cycle for autotrophic CO2 fixation in ε-proteobacteria. Since ε-proteobacteria closely related to these two organisms are important in many habitats, such as hydrothermal vents, oxic-sulfidic interfaces, or oilfields, these results suggest that autotrophic CO2 fixation via the reductive tricarboxylic acid cycle might be more important than previously considered.

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Cloning and Expression Analysis of ATP-Citrate Lyase Genes from Sugarcane

ACTA AGRONOMICA SINICA ◽

10.3724/sp.j.1006.2012.02024 ◽

2013 ◽

Vol 38 (11) ◽

pp. 2024-2033 ◽

Cited By ~ 3

Author(s):

Chang-Ning LI ◽

Qian NONG ◽

Qin-Liang TAN ◽

SRIVASTAVA Manoj Kumar ◽

Li-Tao YANG ◽

...

Keyword(s):

Expression Analysis ◽

Cloning And Expression ◽

Atp Citrate Lyase ◽

Citrate Lyase

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Acetyl-CoA is produced by the citrate synthase homology module of ATP-citrate lyase

Nature Structural & Molecular Biology ◽

10.1038/s41594-021-00624-3 ◽

2021 ◽

Author(s):

Kenneth Verstraete ◽

Koen H. G. Verschueren ◽

Ann Dansercoer ◽

Savvas N. Savvides

Keyword(s):

Citrate Synthase ◽

Atp Citrate Lyase ◽

Acetyl Coa ◽

Citrate Lyase ◽

Homology Module

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IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R

Cell Death and Disease ◽

10.1038/s41419-021-03833-2 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Chenyang Qiao ◽

Wenjie Huang ◽

Jie Chen ◽

Weibo Feng ◽

Tongyue Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Growth Factor ◽

Cancer Metastasis ◽

Combined Treatment ◽

Insulin Like Growth Factor ◽

Atp Citrate Lyase ◽

Citrate Lyase ◽

Elevated Expression ◽

Igf1r Inhibitor ◽

Colorectal Cancer Metastasis

AbstractMetastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.

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