Regulation of S-Adenosylhomocysteine Hydrolase by Lysine Acetylation

Wang, Yun; Kavran, Jennifer M.; Chen, Zan; Karukurichi, Kannan R.; Leahy, Daniel J.; Cole, Philip A.

doi:10.1074/jbc.m114.597153

Cited by 26 publications

(24 citation statements)

References 81 publications

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“…To this end, we setup experiment with neuronal cells transiently over‐expressing SAH hydrolase, the only known enzyme to catalyze the breakdown of SAH and efficiently reducing its intracellular levels (Wang et al ., ). These studies showed that SAH hydrolase over‐expressing cells were protected from the HHcy‐dependent 5LO upregulation and Aβ elevation whereby rescuing the HHcy‐dependent reduction in all 3 methyltransferase enzymes and 5LO hypomethylation.…”

Section: Discussionmentioning

confidence: 97%

Homocysteine modulates 5-lipoxygenase expression level via DNA methylation

Barrero

Gupta

et al. 2016

Aging Cell

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SummaryElevated levels of homocysteinemia (Hcy), a risk factor for late‐onset Alzheimer's disease (AD), have been associated with changes in cell methylation. Alzheimer's disease is characterized by an upregulation of the 5‐lipoxygenase (5LO), whose promoter is regulated by methylation. However, whether Hcy activates 5LO enzymatic pathway by influencing the methylation status of its promoter remains unknown. Brains from mice with high Hcy were assessed for the 5LO pathway and neuronal cells exposed to Hcy implemented to study the mechanism(s) regulating 5LO expression levels and the effect on amyloid β formation. Diet‐ and genetically induced high Hcy resulted in 5LO protein and mRNA upregulation, which was associated with a significant increase of the S‐adenosylhomocysteine (SAH)/S‐adenosylmethionine ratio, and reduced DNA methyltrasferases and hypomethylation of 5‐lipoxygenase DNA. In vitro studies confirmed these results and demonstrated that the mechanism involved in the Hcy‐dependent 5LO activation and amyloid β formation is DNA hypomethylation secondary to the elevated levels of SAH. Taken together these findings represent the first demonstration that Hcy directly influences 5LO expression levels and establish a previously unknown cross talk between these two pathways, which is highly relevant for AD pathogenesis. The discovery of such a novel link not only provides new mechanistic insights in the neurobiology of Hcy, but most importantly new therapeutic opportunities for the individuals bearing this risk factor for the disease.

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Section: Discussionmentioning

confidence: 97%

Homocysteine modulates 5-lipoxygenase expression level via DNA methylation

Barrero

Gupta

et al. 2016

Aging Cell

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“…High levels of EF-1-α-1 have been associated with survival (50) and downregulation of EF-1-α-1 expression resulted in cell death (51). SAHH 3 is an NAD + -dependent tetrameric enzyme that catalyzes the breakdown of S-adenosylhomocysteine to adenosine and homocysteine, and is therefore important in cell growth and regulation of gene expression (52). Loss of SAHH function may result in global inhibition of cellular methyltransferase enzymes due to S-adenosylhomocysteine accumulation (52).…”

Section: Discussionmentioning

confidence: 99%

“…SAHH 3 is an NAD + -dependent tetrameric enzyme that catalyzes the breakdown of S-adenosylhomocysteine to adenosine and homocysteine, and is therefore important in cell growth and regulation of gene expression (52). Loss of SAHH function may result in global inhibition of cellular methyltransferase enzymes due to S-adenosylhomocysteine accumulation (52). Acidic ribosomal phosphoprotein P0 is a structural component of the ribosome of all organisms.…”

Section: Discussionmentioning

confidence: 99%

Label-free LC-MS/MS shotgun proteomics to investigate the anti-inflammatory effect of rCC16

Pang

Bai

et al. 2016

Molecular Medicine Reports

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Clara cell protein (CC16) is an anti-inflammatory protein, which is expressed in the airway epithelium. It is involved in the development of airway inflammatory diseases, including chronic obstructive pulmonary disease and asthma. However, the exact molecular mechanism underlying its anti-inflammatory action remains to be fully elucidated. The aim of the present study was to define the protein profiles of the anti-inflammatory effect of CC16 in lipopolysaccharide (LPS)-treated rat tracheal epithelial (RTE) cells using shotgun proteomics. Protein extracts were obtained from control RTE cells, RTE cells treated with LPS and RTE cells treated with LPS and recombinant CC16 (rCC16). Subsequent label-free quantification and bioinformatics analyses identified 12 proteins that were differentially expressed in the three treatment groups as a cluster of five distinct groups according to their molecular functions. Five of the twelve proteins were revealed to be associated with the cytoskeleton: Matrix metalloproteinase-9, myosin heavy chain 10, actin-related protein-3 homolog, elongation factor 1-α-1 (EF-1-α-1), and acidic ribosomal phosphoprotein P0. Five of the twelve proteins were associated with cellular proliferation: DNA-dependent protein kinase catalytic subunit, EF-1-α-1, tyrosine 3-monooxygenase, caspase recruitment domain (CARD) protein 12 and adenosylhomocysteinase (SAHH) 3. Three proteins were associated with gene regulation: EF-1-α-1, SAHH 3 and acidic ribosomal phosphoprotein P0. Three proteins were associated with inflammation: Tyrosine 3-monooxygenase, CARD protein 12 and statin-related protein. ATPase (H+-transporting, V1 subunit A, isoform 1) was revealed to be associated with energy metabolism, and uridine diphosphate glycosyltransferase 1 family polypeptide A8 with drug metabolism and detoxification. The identified proteins were further validated using reverse transcription-quantitative polymerase chain reaction. These protein profiles, and their interacting protein network, may facilitate the elucidation of the molecular mechanisms underlying the anti-inflammatory effects of CC16.

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“…Crystallographic studies of proteins containing multiple modifications have been successfully addressed with cell-free protein synthesis (Wakamori et al . 2015) and EPL (Wang et al . 2014b).…”

Section: Protein Engineering Approaches For Tackling Outstanding Cmentioning

confidence: 99%

“…2006), enzyme catalysis (Torbeev et al . 2011; Wang et al . 2014b) and protein–protein interactions (Lu et al .…”

Section: Protein Engineering Approaches For Tackling Outstanding Cmentioning

confidence: 99%

A molecular engineering toolbox for the structural biologist

Debelouchina

Muir

2017

Quart. Rev. Biophys.

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Exciting new technological developments have pushed the boundaries of structural biology, and have enabled studies of biological macromolecules and assemblies that would have been unthinkable not long ago. Yet, the enhanced capabilities of structural biologists to pry into the complex molecular world have also placed new demands on the abilities of protein engineers to reproduce this complexity into the test tube. With this challenge in mind, we review the contents of the modern molecular engineering toolbox that allow the manipulation of proteins in a site-specific and chemically well-defined fashion. Thus, we cover concepts related to the modification of cysteines and other natural amino acids, native chemical ligation, intein and sortase-based approaches, amber suppression, as well as chemical and enzymatic bio-conjugation strategies. We also describe how these tools can be used to aid methodology development in X-ray crystallography, nuclear magnetic resonance, cryo-electron microscopy and in the studies of dynamic interactions. It is our hope that this monograph will inspire structural biologists and protein engineers alike to apply these tools to novel systems, and to enhance and broaden their scope to meet the outstanding challenges in understanding the molecular basis of cellular processes and disease.

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Regulation of S-Adenosylhomocysteine Hydrolase by Lysine Acetylation

Cited by 26 publications

References 81 publications

Homocysteine modulates 5-lipoxygenase expression level via DNA methylation

Homocysteine modulates 5-lipoxygenase expression level via DNA methylation

Label-free LC-MS/MS shotgun proteomics to investigate the anti-inflammatory effect of rCC16

A molecular engineering toolbox for the structural biologist

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