Acetylation of proximal cysteine-lysine pairs by alcohol metabolism.

Alcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. These factors alter proteomic and epigenetic marks, including alcohol-induced protein acetylation, which is a key post-translational modification (PTM) that regulates hepatic metabolism and is associated with the pathogenesis of alcohol-associated liver disease (ALD). Recent evidence suggests lysine acetylation occurs when a proximal cysteine residue is within ∼15 Å of a lysine residue, referred to as a cysteine-lysine (Cys-Lys) pair.

Quantifying Protein Acetylation in Diabetic Nephropathy from Formalin-Fixed Paraffin-Embedded Tissue.

Purpose: Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of chronic kidney disease and end-stage renal disease. One potential mechanism underlying cellular dysfunction contributing to kidney disease is aberrant protein post-translational modifications. Lysine acetylation is associated with cellular metabolic flux and is thought to be altered in patients with diabetes and dysfunctional renal metabolism.

Click chemistry-based thiol redox proteomics reveals significant cysteine reduction induced by chronic ethanol consumption.

In the U.S., alcohol-associated liver disease (ALD) impacts millions of people and is a major healthcare burden.

Neuronal SIRT3 Deletion Predisposes to Female-Specific Alterations in Cellular Metabolism, Memory, and Network Excitability.

Mitochondrial dysfunction is an early event in the pathogenesis of neurologic disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases.

Redox state and the sirtuin deacetylases are major factors that regulate the acetylation status of the stress protein NQO1.

The stress induced protein NQO1 can participate in a wide range of biological pathways which are dependent upon the interaction of NQO1 with protein targets. Many of the protein-protein interactions involving NQO1 have been shown to be regulated by the pyridine nucleotide redox balance. NQO1 can modify its conformation as a result of redox changes in pyridine nucleotides and sites on the C-terminal and helix seven regions of NQO1 have been identified as potential areas that may be involved in redox-dependent protein-protein interactions.

Biochemical Mechanisms of Sirtuin-Directed Protein Acylation in Hepatic Pathologies of Mitochondrial Dysfunction.

Mitochondrial protein acetylation is associated with a host of diseases including cancer, Alzheimer's, and metabolic syndrome. Deciphering the mechanisms regarding how protein acetylation contributes to disease pathologies remains difficult due to the complex diversity of pathways targeted by lysine acetylation. Specifically, protein acetylation is thought to direct feedback from metabolism, whereby nutritional status influences mitochondrial pathways including beta-oxidation, the citric acid cycle, and the electron transport chain.

Extracellular superoxide dismutase (EC-SOD) R213G variant reduces mitochondrial ROS and preserves mitochondrial function in bleomycin-induced lung injury: EC-SOD R213G variant and intracellular redox regulation.

Extracellular superoxide dismutase (EC-SOD) is highly expressed in the lung and vasculature. A common human single nucleotide polymorphism (SNP) in the matrix binding region of EC-SOD leads to a single amino acid substitution, R213G, and alters EC-SOD tissue binding affinity. The change in tissue binding affinity redistributes EC-SOD from tissue to extracellular fluids.

Proteomic analysis of alcohol-associated hepatitis reveals glycoprotein NMB (GPNMB) as a novel hepatic and serum biomarker.

Alcohol consumption remains a leading cause of liver disease worldwide, resulting in a complex array of hepatic pathologies, including steatosis, steatohepatitis, and cirrhosis. Individuals who progress to a rarer form of alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), require immediate life-saving intervention in the form of liver transplantation. Rapid onset of AH is poorly understood and the metabolic mechanisms contributing to the progression to liver failure remain undetermined.

Biochemical genesis of enzymatic and non-enzymatic post-translational modifications.

Post-translational modifications (PTMs) alter protein structure, function, and localization and play a pivotal role in physiological and pathophysiological conditions. Many PTMs arise from endogenous metabolic intermediates and serve as sensors for metabolic feedback to maintain cell growth and homeostasis. A key feature to PTMs is their biochemical genesis, which can result from either non-enzymatic adduction (nPTMs) or through enzyme-catalyzed reactions (ePTMs).

A redox-mediated conformational change in NQO1 controls binding to microtubules and α-tubulin acetylation.

The localization of NQO1 near acetylated microtubules has led to the hypothesis that NQO1 may work in concert with the NAD-dependent deacetylase SIRT2 to regulate acetyl α-tubulin (K) levels on microtubules. NQO1 catalyzes the oxidation of NADH to NAD and may supplement levels of NAD near microtubules to aid SIRT2 deacetylase activity. While HDAC6 has been shown to regulate the majority of microtubule acetylation at K, SIRT2 is also known to modulate microtubule acetylation (K) in the perinuclear region.

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity.

Objective: Cardiac troponin I (cTnI) is an essential physiological and pathological regulator of cardiac relaxation. Significant to this regulation, the post-translational modification of cTnI through phosphorylation functions as a key mechanism to accelerate myofibril relaxation. Similar to phosphorylation, post-translational modification by acetylation alters amino acid charge and protein function.

Toxic consequences and oxidative protein carbonylation from chloropicrin exposure in human corneal epithelial cells.

Chloropicrin (CP), a warfare agent now majorly used as a soil pesticide, is a strong irritating and lacrimating compound with devastating toxic effects. To elucidate the mechanism of its ocular toxicity, toxic effects of CP (0-100 μM) were studied in primary human corneal epithelial (HCE) cells. CP exposure resulted in reduced HCE cell viability and increased apoptotic cell death with an up-regulation of cleaved caspase-3 and poly ADP ribose polymerase indicating their contribution in CP-induced apoptotic cell death.

Defining decreased protein succinylation of failing human cardiac myofibrils in ischemic cardiomyopathy.

Succinylation is a post-translational modification of protein lysine residues with succinyl groups derived from succinyl CoA. Succinylation is considered a significant post-translational modification with the potential to impact protein function which is highly conserved across numerous species. The role of succinylation in the heart, especially in heart failure and myofibril mechanics, remains largely unexplored.

Investigating RNA expression profiles altered by nicotinamide mononucleotide therapy in a chronic model of alcoholic liver disease.

Background: Chronic alcohol consumption is a significant cause of liver disease worldwide. Several biochemical mechanisms have been linked to the initiation and progression of alcoholic liver disease (ALD) such as oxidative stress, inflammation, and metabolic dysregulation, including the disruption of NAD/NADH. Indeed, an ethanol-mediated reduction in hepatic NAD levels is thought to be one factor underlying ethanol-induced steatosis, oxidative stress, steatohepatitis, insulin resistance, and inhibition of gluconeogenesis.

Aspirin inhibits TGFβ2-induced epithelial to mesenchymal transition of lens epithelial cells: selective acetylation of K56 and K122 in histone H3.

Posterior capsule opacification (PCO) is a complication after cataract surgery that can disrupt vision. The epithelial to mesenchymal transition (EMT) of lens epithelial cells (LECs) in response to transforming growth factor β2 (TGFβ2) has been considered an obligatory mechanism for PCO. In this study, we tested the efficacy of aspirin in inhibiting the TGFβ2-mediated EMT of human LECs, LECs in human lens capsular bags, and lensectomized mice.

SNARE proteins rescue impaired autophagic flux in Down syndrome.

Down syndrome (DS) is a chromosomal disorder caused by trisomy of chromosome 21 (Ts21). Unbalanced karyotypes can lead to dysfunction of the proteostasis network (PN) and disrupted proteostasis is mechanistically associated with multiple DS comorbidities. Autophagy is a critical component of the PN that has not previously been investigated in DS.

Lysine malonylation and propionylation are prevalent in human lens proteins.

Acylated lysine residues represent major chemical modifications in proteins. We investigated the malonylation and propionylation of lysine residues (MalK, PropK) in the proteins of aging human lenses. Western blot results showed that the two modifications are present in human lens proteins.

Lipid peroxidation derived reactive aldehydes in alcoholic liver disease.

Lipid peroxidation is a known consequence of oxidative stress and is thought to play a key role in numerous disease pathologies, including alcoholic liver disease (ALD). The overaccumulation of lipid peroxidation products during chronic alcohol consumption results in pathogenic lesions on protein, DNA, and lipids throughout the cell. Molecular adducts due to secondary end products of lipid peroxidation impact a host of biochemical processes, including inflammation, antioxidant defense, and metabolism.

Multi-omics Analysis of Liver Infiltrating Macrophages Following Ethanol Consumption.

Alcoholic liver disease (ALD) is a significant health hazard and economic burden affecting approximately 10 million people in the United States. ALD stems from the production of toxic-reactive metabolites, oxidative stress and fat accumulation in hepatocytes which ultimately results in hepatocyte death promoting hepatitis and fibrosis deposition. Monocyte-derived infiltrating Ly6C and Ly6C macrophages are instrumental in perpetuating and resolving the hepatitis and fibrosis associated with ALD pathogenesis.

The absence of SIRT3 and SIRT5 promotes the acetylation of lens proteins and improves the chaperone activity of α-crystallin in mouse lenses.

Acetylation of lysine residues occurs in lens proteins. Previous studies have shown an improvement in the chaperone activity of αA-crystallin upon acetylation. Sirtuins are NAD-dependent enzymes that can deacylate proteins.

Succinylation Is a Gain-of-Function Modification in Human Lens αB-Crystallin.

Acylation of lysine residues is a common post-translational modification of cellular proteins. Here, we show that lysine succinylation, a type of acylation, occurs in human lens proteins. All of the major crystallins exhibited N-succinyllysine (SuccK) residues.

Quantifying Competition among Mitochondrial Protein Acylation Events Induced by Ethanol Metabolism.

Mitochondrial dysfunction is one of many key factors in the etiology of alcoholic liver disease (ALD). Lysine acetylation is known to regulate numerous mitochondrial metabolic pathways, and recent reports demonstrate that alcohol-induced protein acylation negatively impacts these processes. To identify regulatory mechanisms attributed to alcohol-induced protein post-translational modifications, we employed a model of alcohol consumption within the context of wild type (WT), sirtuin 3 knockout (SIRT3 KO), and sirtuin 5 knockout (SIRT5 KO) mice to manipulate hepatic mitochondrial protein acylation.

SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain.

SIRT3, the primary mitochondrial deacetylase, plays a significant role in enhancing the function of mitochondrial proteins. Downregulation of SIRT3 is a key component of metabolic syndrome, a precondition for obesity, diabetes and cardiovascular diseases. In this study, we examined the effects of brain mitochondrial protein hyperacetylation in western diet-fed Sirt3 mice, a model for metabolic syndrome.