Thomas D. Hurley

Bio: Thomas D. Hurley is an academic researcher from Indiana University. The author has contributed to research in topics: Aldehyde dehydrogenase & Alcohol dehydrogenase. The author has an hindex of 49, co-authored 135 publications receiving 7497 citations. Previous affiliations of Thomas D. Hurley include Indiana University – Purdue University Indianapolis & Anschutz Medical Campus.

Activation of Aldehyde Dehydrogenase-2 Reduces Ischemic Damage to the Heart

Abstract: There is substantial interest in the development of drugs that limit the extent of ischemia-induced cardiac damage caused by myocardial infarction or by certain surgical procedures. Here, using an unbiased proteomic search, we identified mitochondrial aldehyde dehydrogenase 2 (ALDH2) as an enzyme whose activation correlates with reduced ischemic heart damage in rodent models. A high-throughput screen yielded a small-molecule activator of ALDH2 (Alda-1) that, when administered to rats before an ischemic event, reduced infarct size by 60%, most likely through its inhibitory effect on the formation of cytotoxic aldehydes. In vitro, Alda-1 was a particularly effective activator of ALDH2*2, an inactive mutant form of the enzyme that is found in 40% of East Asian populations. Thus, pharmacologic enhancement of ALDH2 activity may be useful for patients with wild-type or mutant ALDH2 who are subjected to cardiac ischemia, such as during coronary bypass surgery.

Glycogen and its metabolism: some new developments and old themes.

Abstract: Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by hormones such as insulin, glucagon and adrenaline (epinephrine). There has been debate over the relative importance of allosteric compared with covalent control of the key biosynthetic enzyme, glycogen synthase, as well as the relative importance of glucose entry into cells compared with glycogen synthase regulation in determining glycogen accumulation. Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogen metabolism that shed light on the mechanism of control; (iii) greater appreciation of the spatial aspects of glycogen metabolism, including more focus on the lysosomal degradation of glycogen; and (iv) glycogen phosphorylation and advances in the study of Lafora disease, which is emerging as a glycogen storage disease.

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

Abstract: Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. ALDH2, as a key enzyme that oxidizes acetaldehyde, is crucial for alcohol metabolism. ALDH1A1 and ALDH3A1 are lens and corneal crystallins, which are essential elements of the cellular defense mechanism against ultraviolet radiation-induced damage in ocular tissues. Many ALDH isozymes are important in oxidizing reactive aldehydes derived from lipid peroxidation and thereby help maintain cellular homeostasis. Increased expression and activity of ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. As a direct consequence of their significant physiological and toxicological roles, inhibitors of the ALDH enzymes have been developed to treat human diseases. This review summarizes known ALDH inhibitors, their mechanisms of action, isozyme selectivity, potency, and clinical uses. The purpose of this review is to 1) establish the current status of pharmacological inhibition of the ALDHs, 2) provide a rationale for the continued development of ALDH isozyme-selective inhibitors, and 3) identify the challenges and potential therapeutic rewards associated with the creation of such agents.

Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

Abstract: We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

Knowledge-based protein secondary structure assignment.

Abstract: We have developed an automatic algorithm STRIDE for protein secondary structure assignment from atomic coordinates based on the combined use of hydrogen bond energy and statistically derived backbone torsional angle information. Parameters of the pattern recognition procedure were optimized using designations provided by the crystallographers as a standard-of-truth. Comparison to the currently most widely used technique DSSP by Kabsch and Sander (Biopolymers 22:2577-2637, 1983) shows that STRIDE and DSSP assign secondary structural states in 58 and 31% of 226 protein chains in our data sample, respectively, in greater agreement with the specific residue-by-residue definitions provided by the discoverers of the structures while in 11% of the chains, the assignments are the same. STRIDE delineates every 11th helix and every 32nd strand more in accord with published assignments.

Ischemia and reperfusion—from mechanism to translation

Abstract: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.

Epidemiology of DSM-5 Alcohol Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions III

Abstract: Importance National epidemiologic information from recently collected data on the newDSM-5classification of alcohol use disorder (AUD) using a reliable, valid, and uniform data source is needed. Objective To present nationally representative findings on the prevalence, correlates, psychiatric comorbidity, associated disability, and treatment ofDSM-5AUD diagnoses overall and according to severity level (mild, moderate, or severe). Design, Setting, and Participants We conducted face-to-face interviews with a representative US noninstitutionalized civilian adult (≥18 years) sample (N = 36 309) as the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC-III). Data were collected from April 2012 through June 2013 and analyzed in October 2014. Main Outcomes and Measures Twelve-month and lifetime prevalences of AUD. Results Twelve-month and lifetime prevalences of AUD were 13.9% and 29.1%, respectively. Prevalence was generally highest for men (17.6% and 36.0%, respectively), white (14.0% and 32.6%, respectively) and Native American (19.2% and 43.4%, respectively), respondents, and younger (26.7% and 37.0%, respectively) and previously married (11.4% and 27.1%, respectively) or never married (25.0% and 35.5%, respectively) adults. Prevalence of 12-month and lifetime severe AUD was greatest among respondents with the lowest income level (1.8% and 1.5%, respectively). Significant disability was associated with 12-month and lifetime AUD and increased with the severity of AUD. Only 19.8% of respondents with lifetime AUD were ever treated. Significant associations were found between 12-month and lifetime AUD and other substance use disorders, major depressive and bipolar I disorders, and antisocial and borderline personality disorders across all levels of AUD severity, with odds ratios ranging from 1.2 (95% CI, 1.08-1.36) to 6.4 (95% CI, 5.76-7.22). Associations between AUD and panic disorder, specific phobia, and generalized anxiety disorder were modest (odds ratios ranged from 1.2 (95% CI, 1.01-1.43) to 1.4 (95% CI, 1.13-1.67) across most levels of AUD severity. Conclusions and Relevance Alcohol use disorder defined byDSM-5criteria is a highly prevalent, highly comorbid, disabling disorder that often goes untreated in the United States. The NESARC-III data indicate an urgent need to educate the public and policy makers about AUD and its treatment alternatives, to destigmatize the disorder, and to encourage those who cannot reduce their alcohol consumption on their own, despite substantial harm to themselves and others, to seek treatment.

Glycosyltransferases: structures, functions, and mechanisms.

Abstract: Glycosyltransferases catalyze glycosidic bond formation using sugar donors containing a nucleoside phosphate or a lipid phosphate leaving group. Only two structural folds, GT-A and GT-B, have been identified for the nucleotide sugar-dependent enzymes, but other folds are now appearing for the soluble domains of lipid phosphosugar-dependent glycosyl transferases. Structural and kinetic studies have provided new insights. Inverting glycosyltransferases utilize a direct displacement S(N)2-like mechanism involving an enzymatic base catalyst. Leaving group departure in GT-A fold enzymes is typically facilitated via a coordinated divalent cation, whereas GT-B fold enzymes instead use positively charged side chains and/or hydroxyls and helix dipoles. The mechanism of retaining glycosyltransferases is less clear. The expected two-step double-displacement mechanism is rendered less likely by the lack of conserved architecture in the region where a catalytic nucleophile would be expected. A mechanism involving a short-lived oxocarbenium ion intermediate now seems the most likely, with the leaving phosphate serving as the base.