Bio

Bio


Dr. Sher received her BA from UC Berkeley and MD from Washington University in St. Louis. She completed Residency in Psychiatry and Fellowship in Psychosomatic Medicine at Stanford University Medical Center. She has been a part of Psychosomatic Medicine Faculty at Stanford since 2013. Her areas of clinical and research interests include psychiatric comorbidities in patients with pulmonary disorders. In particular, she specializes in mental health of patients with cystic fibrosis as well as lung and heart transplant patients. She consults on patients hospitalized on medical and surgical units as well as sees patients in outpatient clinics. She serves as a Mental Health Coordinator for the Adult Cystic Fibrosis Clinic.

Clinical Focus


  • Psychiatry
  • Psychosomatic Medicine
  • Lung Transplant Psychiatry

Academic Appointments


  • Clinical Associate Professor, Psychiatry and Behavioral Sciences

Administrative Appointments


  • Mental Health Coordinator, Adult Cystic Fibrosis Clinic (2016 - Present)
  • Psychosomatic Medicine Associate Fellowship Director, Psychosomatic Medicine (2015 - Present)

Boards, Advisory Committees, Professional Organizations


  • Ethics Committee, Stanford University Medical Center (2013 - Present)
  • Academy of Psychosomatic Medicine, Member (2012 - Present)

Professional Education


  • Medical Education:Washington University in St Louis Registrar (2007) MO
  • Board Certification: Psychosomatic Medicine, American Board of Psychiatry and Neurology (2015)
  • Board Certification: Psychiatry, American Board of Psychiatry and Neurology (2012)
  • Fellowship:Stanford University - Dept of Psychiatry (2012) CA
  • Residency:Stanford University - Dept of Psychiatry (2011) CA

Research & Scholarship

Clinical Trials


  • Valproic Acid for Treatment of Hyperactive or Mixed Delirium in ICU Not Recruiting

    Delirium is the most often encountered psychiatric diagnosis in the general hospital, with incidence up to 85% in the intensive care unit (ICU) setting and with significant consequences on patients' morbidity and mortality. Currently, although not FDA approved, antipsychotics are often considered the first-line pharmacological treatment. However, there can be limitations to their use, including side effects or lack of efficacy. Valproic acid (VPA) is one of the alternatives at times used in such patients which from limited case series data appears to be helpful and tolerated. VPA can provide relief from agitation that poses a threat to the safety and recovery of the patient. Moreover, mechanistically it addresses the neurochemical and cellular abnormalities inherent in delirium (it has NMDA-antagonist, anti-dopaminergic, GABAergic,anti-inflammatory, anti-apoptotic, and histone deacetylase inhibitor properties, among others). The purpose of this study is to evaluate the efficacy and tolerability of the VPA in the first known to us randomized controlled trial.

    Stanford is currently not accepting patients for this trial. For more information, please contact Shengchun Wang, Ph.D, 518-334-2513.

    View full details

Teaching

Publications

All Publications


  • DIGNITY THERAPY IN PERSONS WITH CF Sher, Y. WILEY. 2019: S72–S73
  • Psychiatric Aspects of Lung Disease in Critical Care CRITICAL CARE CLINICS Sher, Y. 2017; 33 (3): 601-+

    Abstract

    Respiratory conditions are some of the most common indications for admission to critical care units. Psychiatric disorders and symptoms are highly comorbid with lung disease. They can occur as a risk factor to lung disease, as a co-occurring condition, as a consequence of a pulmonary condition, or as a treatment side effect either from medications or assistive devices. Patients can experience a myriad of mood, anxiety, and cognitive disorder symptoms and conditions in critical care units. Intensivists and psychiatrists must be aware of the interplay between pulmonary and psychiatric symptoms as well as medication effects and interactions.

    View details for PubMedID 28601136

  • Psychiatric Aspects of Organ Transplantation in Critical Care: An Update CRITICAL CARE CLINICS Sher, Y., Zimbrean, P. 2017; 33 (3): 659-+

    Abstract

    Transplant patients face challenging medical journeys, with many detours to the intensive care unit. Before and after transplantation, they have significant psychological and cognitive comorbidities, which decrease their quality of life and potentially compromise their medical outcomes. Critical care staff are essential in these journeys. Being cognizant of relevant psychosocial and mental health aspects of transplant patients' experiences can help critical care personnel take comprehensive care of these patients. This knowledge can empower them to understand their patients' psychological journeys, recognize patients' mental health needs, provide initial interventions, and recognize need for expert consultations.

    View details for PubMedID 28601140

  • Delirium after lung transplantation: Association with recipient characteristics, hospital resource utilization, and mortality. Clinical transplantation Sher, Y., Mooney, J., Dhillon, G., Lee, R., Maldonado, J. R. 2017; 31 (5)

    Abstract

    Delirium is associated with increased morbidity and mortality. The factors associated with post-lung transplant delirium and its impact on outcomes are under characterized.The medical records of 163 consecutive adult lung transplant recipients were reviewed for delirium within 5 days (early-onset) and 30 hospital days (ever-onset) post-transplantation. A multivariable logistic regression model assessed factors associated with delirium. Multivariable negative binomial regression and Cox proportional hazards models assessed the association of delirium with ventilator duration, intensive care unit (ICU) length of stay (LOS), hospital LOS and one-year mortality.Thirty six % developed early-onset and 44% - ever-onset delirium. Obesity (OR 6.35, 95% CI 1.61-24.98) and bolused benzodiazepines within the first post-operative day (OR 2.28, 95% CI 1.07-4.89) were associated with early-onset delirium. Early-onset delirium was associated with longer adjusted mechanical ventilation duration (p=0.001), ICU LOS (p<0.001), and hospital LOS (p=0.005). Ever-onset delirium was associated with longer ICU (p<0.001) and hospital LOS (p<0.001). After adjusting for clinical variables, delirium was not significantly associated with one-year mortality (early-onset HR 1.65, 95% CI 0.67-4.03; ever-onset HR 1.70, 95% CI 0.63-4.55).Delirium is common after lung transplant surgery and associated with increased hospital resources. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/ctr.12966

    View details for PubMedID 28314081

  • PSYCHIATRIST AS A MENTAL HEALTH COORDINATOR: THE STANFORD MODEL Sher, Y., Dvorak, M. WILEY-BLACKWELL. 2016: 155
  • THE PSYCHOLOGICAL AND EXISTENTIAL ASPECTS OF GROWING OLD WITH CYSTIC FIBROSIS Sher, Y. WILEY-BLACKWELL. 2016: 138
  • Frontal Lobe Epilepsy: A Primer for Psychiatrists and a Systematic Review of Psychiatric Manifestations. Psychosomatics Gold, J. A., Sher, Y., Maldonado, J. R. 2016; 57 (5): 445-464

    Abstract

    Frontal lobe epilepsy (FLE) can masquerade as a primary psychiatric condition, be misdiagnosed in-lieu of a true psychiatric disorder, or may be comorbid with psychiatric illness.To (1) qualitatively review psychiatric manifestations of FLE and (2) to systematically review the cases/case series of psychiatric manifestations of FLE presented in the literature to date.A systematic review of the literature was performed following the PRISMA guidelines and using PubMed/Medline, PsychInfo, and Cochrane database of systematic reviews to identify cases and case series of psychiatric manifestations of FLE.A total of 35 separate articles were identified. Further, 17 patients primarily presented with psychosis, 33 with affective symptoms, and 16 with personality changes. Also, 62% of cases were males and 38% were females. Ages ranged from 2-83 years with the average age of 32.7. Prior psychiatric history was reported in 27.3% of cases. Causes of seizure were known in 53%, with the most common causes being dysplasia and tumor. Only 6 cases (<10%) did not have electroencephalographic correlations. Psychiatric manifestations were primarily ictal in 74.3% of the cases. Associated manifestations included motor (63.6%), cognitive (34.8%), and medical (9.0%) findings. Surgery was required in 31.8% of the cases, whereas others were treated with medications alone. All, but 3, patients were seizure free and saw an improvement in symptoms with treatment.Given the complexity and multifunctionality of the frontal lobes, FLE can present with complex, psychiatric manifestations, with associated motor, cognitive, and medical changes; thus, psychiatrists should keep FLE on the differential diagnosis of complex neuropsychiatric cases.

    View details for DOI 10.1016/j.psym.2016.05.005

    View details for PubMedID 27494984

  • Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review PSYCHOSOMATICS Sher, Y., Cramer, A. C., Ament, A., Lolak, S., Maldonado, J. R. 2015; 56 (6): 615-625

    Abstract

    Delirium is the most often encountered psychiatric diagnosis in the general hospital, with an incidence of up to 82% in the intensive care unit setting and with significant detrimental effects on patients' morbidity and mortality. Antipsychotics are often considered the first-line pharmacological treatment of delirium, but their use may be limited by lack of efficacy, existing contraindications (e.g., prolonged QTc intervals), or resulting side effects (e.g., akathisia). Valproic acid (VPA) is a potential alternative or adjunct treatment. It has multiple mechanisms of action, including effects on neurotransmitter modulation, neuroinflammation, oxidative stress, and transcription, all of which are implicated in the pathophysiology of delirium. Yet, data on the use of this agent in delirium are limited.In this article, we discuss postulated mechanisms of VPA action that provide a theoretical basis for its use in the treatment of hyperactive and mixed type delirium, based on the known and theorized pathophysiology of delirium. We also discuss potential side effects and considerations with use of VPA.VPA has multiple modulatory effects on neurotransmitter systems, inflammation, oxidative stress, and transcriptional changes implicated in pathophysiology of delirium. When carefully chosen, VPA can be an effective and well-tolerated treatment option for the management of hyperactive and mixed type delirium. Randomized controlled trials are needed to establish tolerability and efficacy of VPA for treatment of delirium.

    View details for Web of Science ID 000366315400002

    View details for PubMedID 26674479

  • The Stanford Integrated Psychosocial Assessment for Transplantation: A Prospective Study of Medical and Psychosocial Outcomes PSYCHOSOMATIC MEDICINE Maldonado, J. R., Sher, Y., Lolak, S., Swendsen, H., Skibola, D., Neri, E., David, E. E., Sullivan, C., Standridge, K. 2015; 77 (9): 1018-1030

    Abstract

    Psychosocial factors may significantly affect post-transplant outcomes. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) was developed as an assessment tool to enhance the pre-transplant psychosocial evaluation.We identified heart, lung, liver, or kidney transplant recipients assessed with the SIPAT pre-transplantation and transplanted between June 1, 2008, and July 31, 2011, at our institution. We analyzed prospectively accumulated psychosocial and medical outcomes at 1 year of follow-up.217 patients were identified and included in the analysis. The primary outcomes of organ failure and mortality occurred in 12 and 21 patients, respectively, and were not significantly associated with the pre-transplant SIPAT scores. On the other hand, SIPAT scores were significantly correlated with the probability of poor medical and psychosocial outcomes (secondary outcomes). In fact, higher SIPAT scores predicted higher rates of rejection episodes (Spearman ρ = 0.15, 95% 95% confidence interval [CI] = 0.02-0.28, p = .023), medical hospitalizations (ρ = 0.29, 95% CI = 0.16-0.41, p < .001), infection rates (p = .020), psychiatric decompensation (p = .005), and support system failure (area under the curve = 0.70, 95% CI = 0.60-0.79, p < .001). The relationship with nonadherence suggested a trend, but no statistical significance was observed (area under the curve = 0.60, 95% CI = 0.50-0.71, p = .058).Study outcomes suggest that SIPAT is a promising pre-transplantation assessment tool that helps identify candidate's areas of psychosocial vulnerability and whose scores are associated with both psychosocial and medical outcomes after transplantation.

    View details for DOI 10.1097/PSY.0000000000000241

    View details for PubMedID 26517474

  • Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale. journal of neuropsychiatry and clinical neurosciences Sher, Y., Miller, A. C., Lolak, S., Ament, A., Maldonado, J. R. 2015; 27 (4): 365-370

    Abstract

    Patients with delirium may fail to respond to standard therapies. Sixteen patients with management-refractory hyperactive delirium responded to adjunctive valproic acid, with complete resolution of hyperactive delirium in 13 cases. A rationale for using valproic acid in such circumstances is discussed.

    View details for DOI 10.1176/appi.neuropsych.14080190

    View details for PubMedID 25803136

  • Prospective Validation Study of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) in Medically Ill Inpatients: A New Scale for the Prediction of Complicated Alcohol Withdrawal Syndrome ALCOHOL AND ALCOHOLISM Maldonado, J. R., Sher, Y., Das, S., Hills-Evans, K., Frenklach, A., Lolak, S., Talley, R., Neri, E. 2015; 50 (5): 509-518

    Abstract

    The prevalence of alcohol use disorders (AUDs) among hospitalized medically ill patients exceeds 40%. Most AUD patients experience uncomplicated alcohol withdrawal syndrome (AWS), requiring only supportive medical intervention, while complicated AWS occurs in up to 20% of cases (i.e. seizures, delirium tremens). We aimed to prospectively test and validate the Prediction of Alcohol Withdrawal Severity Scale (PAWSS), a new tool to identify patients at risk for developing complicated AWS, in medically ill hospitalized patients.We prospectively considered all subjects hospitalized to selected general medicine and surgery units over a 12-month period. Participants were assessed independently and blindly on a daily basis with PAWSS, Clinical Institute Withdrawal Assessment-Alcohol, Revised (CIWA-Ar) and clinical monitoring throughout their admission to determine the presence and severity of AWS.Four hundred and three patients were enrolled in the study. Patients were grouped by PAWSS score: Group A (PAWSS < 4; considered at low risk for complicated AWS); Group B (PAWSS ≥ 4; considered at high risk for complicated AWS). The results of this study suggest that, using a PAWSS cutoff of 4, the tool's sensitivity for identifying complicated AWS is 93.1% (95%CI[77.2, 99.2%]), specificity is 99.5% (95%CI[98.1, 99.9%]), positive predictive value is 93.1% and negative predictive value is 99.5%; and has excellent inter-rater reliability with Lin's concordance coefficient of 0.963 (95% CI [0.936, 0.979]).PAWSS has excellent psychometric characteristics and predictive value among medically ill hospitalized patients, helping clinicians identify those at risk for complicated AWS and allowing for prevention and timely treatment of complicated AWS.

    View details for DOI 10.1093/alcalc/agv043

    View details for Web of Science ID 000363934400004

    View details for PubMedID 25999438

  • An Insatiable Desire for Tofu: A Case of Restless Legs and Unusual Pica in Iron Deficiency Anemia PSYCHOSOMATICS Sher, Y., Maldonado, J. R. 2014; 55 (6): 680-685

    View details for Web of Science ID 000346182000019

    View details for PubMedID 25497506

  • The "Prediction of Alcohol Withdrawal Severity Scale" (PAWSS): Systematic literature review and pilot study of a new scale for the prediction of complicated alcohol withdrawal syndrome. Alcohol Maldonado, J. R., Sher, Y., Ashouri, J. F., Hills-Evans, K., Swendsen, H., Lolak, S., Miller, A. C. 2014; 48 (4): 375-390

    Abstract

    To date, no screening tools for alcohol withdrawal syndromes (AWS) have been validated in the medically ill. Although several tools quantify the severity of AWS (e.g., Clinical Institute Withdrawal Assessment for Alcohol [CIWA]), none identify subjects at risk of AWS, thus missing the opportunity for timely prophylaxis. Moreover, there are no validated tools for the prediction of complicated (i.e., moderate to severe) AWS in the medically ill.Our goals were (1) to conduct a systematic review of the published literature on AWS to identify clinical factors associated with the development of AWS, (2) to use the identified factors to develop a tool for the prediction of alcohol withdrawal among patients at risk, and (3) to conduct a pilot study to assess the validity of the tool.For the creation of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS), we conducted a systematic literature search using PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines for clinical factors associated with the development of AWS, using PubMed, PsychInfo, MEDLINE, and Cochrane Databases. Eligibility criteria included: (i) manuscripts dealing with human subjects, age 18 years or older, (ii) manuscripts directly addressing descriptions of AWS or its predisposing factors, including case reports, naturalistic case descriptions, and all types of clinical trials (e.g., randomized, single-blind, or open label studies), (iii) manuscripts describing characteristics of alcohol use disorder (AUD), and (iv) manuscripts dealing with animal data (which were considered only if they directly dealt with variables described in humans). Obtained data were used to develop the Prediction of Alcohol Withdrawal Severity Scale, in order to assist in the identification of patients at risk for complicated AWS. A pilot study was conducted to assess the new tool's psychometric qualities on patients admitted to a general inpatient medicine unit over a 2-week period, who agreed to participate in the study. Blind to PAWSS results, a separate group of researchers retrospectively examined the medical records for evidence of AWS.The search produced 2802 articles describing factors potentially associated with increased risk for AWS, increased severity of withdrawal symptoms, and potential characteristics differentiating subjects with various forms of AWS. Of these, 446 articles met inclusion criteria and underwent further scrutiny, yielding a total of 233 unique articles describing factors predictive of AWS. A total of 10 items were identified as correlated with complicated AWS (i.e., withdrawal hallucinosis, withdrawal-related seizures, and delirium tremens) and used to construct the PAWSS. During the pilot study, a total of 68 subjects underwent evaluation with PAWSS. In this pilot sample the sensitivity, specificity, and positive and negative predictive values of PAWSS were 100%, using the threshold score of 4.The results of the literature search identified 10 items which may be correlated with risk for complicated AWS. These items were assembled into a tool to assist in the identification of patients at risk: PAWSS. The results of this pilot study suggest that PAWSS may be useful in identifying risk of complicated AWS in medically ill, hospitalized individuals. PAWSS is the first validated tool for the prediction of severe AWS in the medically ill and its use may aid in the early identification of patients at risk for complicated AWS, allowing for prophylaxis against AWS before severe alcohol withdrawal syndromes develop.

    View details for DOI 10.1016/j.alcohol.2014.01.004

    View details for PubMedID 24657098

  • THE STANFORD INTEGRATED PSYCHOSOCIAL ASSESSMENT FOR TRANSPLANTATION (SIPAT): A PROSPECTIVE STUDY OF MEDICAL & PSYCHOSOCIAL OUTCOMES. Maldonado, J. R., Sher, Y., Lolak, S. LIPPINCOTT WILLIAMS & WILKINS. 2014: A70–A71
  • THE "PREDICTION OF ALCOHOL WITHDRAWAL SEVERITY SCALE" (PAWSS): A NEW SCALE FOR THE PREDICTION OF MODERATE TO SEVERE ALCOHOL WITHDRAWAL SYNDROME. Maldonado, J. R., Sher, Y., Ashouri, J. LIPPINCOTT WILLIAMS & WILKINS. 2014: A38
  • VALPROIC ACID AS AN ADJUNCT TREATMENT FOR HYPERACTIVE DELIRIUM: POSTULATED MECHANISMS OF DELIRIOLYTIC ACTION AND CASE SERIES Sher, Y. I., Miller, A. C., Lolak, S., Maldonado, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2014: A39
  • STANFORD INTEGRATED PSYCHOSOCIAL ASSESSMENT FOR TRANSPLANTATION (SIPAT) - A NEW SCALE TO PREDICT PSYCHOSOCIAL & MEDICAL OUTCOMES IN ORGAN TRANSPLANT CANDIDATES Maldonado, J. R., Sher, Y., Lolak, S., Skibola, D., Sullivan, C., Standridge, K., David, E. SPRINGER. 2013: S250
  • THE "PREDICTION OF ALCOHOL WITHDRAWAL SEVERITY SCALE" (PAWSS): A NEW SCALE FOR THE PREDICTION OF MODERATE TO SEVERE ALCOHOL WITHDRAWAL SYNDROME Maldonado, J. R., Sher, Y., Lolak, S., Kissner, L. SPRINGER. 2013: S97
  • The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT): A New Tool for the Psychosocial Evaluation of Pre-Transplant Candidates PSYCHOSOMATICS Maldonado, J. R., Dubois, H. C., David, E. E., Sher, Y., Lolak, S., Dyal, J., Witten, D. 2012; 53 (2): 123-132

    Abstract

    While medical criteria have been well established for each end-organ system, psychosocial listing criteria are less standardized. To address this limitation, we developed and tested a new assessment tool: the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT).The SIPAT was developed from a comprehensive review of the literature on the psychosocial factors that impact transplant outcomes. Five examiners blindly applied the SIPAT to 102 randomly selected transplant cases, including liver, heart, and lung patients. After all subject's files had been rated by the examiners, the respective transplant teams provided the research team with the patient's outcome data.Univariate logistic regression models were fit in order to predict the transplant psychosocial outcome (positive or negative) using each rater's SIPAT scores. These results show that SIPAT scores are highly predictive of the transplant psychosocial outcome (P < 0.0001). The instrument has excellent inter-rater reliability (Pearson's correlation coefficient = 0.853), even among novice raters.The SIPAT is a comprehensive screening tool to assist in the psychosocial assessment of organ transplant candidates. Its strengths includes the standardization of the evaluation process and its ability to identify subjects who are at risk for negative outcomes after the transplant, in order to allow for the development of interventions directed at improving the patient's candidacy. Our goal is that the SIPAT, in addition to a set of agreed upon minimal psychosocial listing criteria, would be used in combination with organ-specific medical listing criteria in order to establish standardized criteria for the selection of transplant recipients.

    View details for PubMedID 22424160

  • The Impact of Depression in Heart Disease CURRENT PSYCHIATRY REPORTS Sher, Y., Lolak, S., Maldonado, J. R. 2010; 12 (3): 255-264

    Abstract

    Depression and heart disease affect millions of people worldwide. Studies have shown that depression is a significant risk factor for new heart disease and that it increases morbidity and mortality in established heart disease. Many hypothesized and studied mechanisms have linked depression and heart disease, including serotonergic pathway and platelet dysfunction, inflammation, autonomic nervous system and hypothalamic-pituitary-adrenal axis imbalance, and psychosocial factors. Although the treatment of depression in cardiac patients has been shown to be safe and modestly efficacious, it has yet to translate into reduced cardiovascular morbidity and mortality. Understanding the impact and mechanisms behind the association of depression and heart disease may allow for the development of treatments aimed at altering the devastating consequences caused by these comorbid illnesses.

    View details for DOI 10.1007/s11920-010-0116-8

    View details for Web of Science ID 000289731700015

    View details for PubMedID 20425289

  • Differences in protonation of ubiquinone and menaquinone in fumarate reductase from Escherichia coli JOURNAL OF BIOLOGICAL CHEMISTRY Maklashina, E., Hellwig, P., Rothery, R. A., Kotlyar, V., Sher, Y., Weiner, J. H., Cecchini, G. 2006; 281 (36): 26655-26664

    Abstract

    Escherichia coli quinol-fumarate reductase operates with both natural quinones, ubiquinone (UQ) and menaquinone (MQ), at a single quinone binding site. We have utilized a combination of mutagenesis, kinetic, EPR, and Fourier transform infrared methods to study the role of two residues, Lys-B228 and Glu-C29, at the quinol-fumarate reductase quinone binding site in reactions with MQ and UQ. The data demonstrate that Lys-B228 provides a strong hydrogen bond to MQ and is essential for reactions with both quinone types. Substitution of Glu-C29 with Leu and Phe caused a dramatic decrease in enzymatic reactions with MQ in agreement with previous studies, however, the succinate-UQ reductase reaction remains unaffected. Elimination of a negative charge in Glu-C29 mutant enzymes resulted in significantly increased stabilization of both UQ-* and MQ-* semiquinones. The data presented here suggest similar hydrogen bonding of the C1 carbonyl of both MQ and UQ, whereas there is different hydrogen bonding for their C4 carbonyls. The differences are shown by a single point mutation of Glu-C29, which transforms the enzyme from one that is predominantly a menaquinol-fumarate reductase to one that is essentially only functional as a succinate-ubiquinone reductase. These findings represent an example of how enzymes that are designed to accommodate either UQ or MQ at a single Q binding site may nevertheless develop sufficient plasticity at the binding pocket to react differently with MQ and UQ.

    View details for DOI 10.1074/jbc.M602938200

    View details for Web of Science ID 000240249500083

    View details for PubMedID 16829675

  • Fumarate reductase and succinate oxidase activity of Escherichia coli complex II homologs are perturbed differently by mutation of the flavin binding domain JOURNAL OF BIOLOGICAL CHEMISTRY Maklashina, E., Iverson, T. M., Sher, Y., Kotlyar, V., Andrell, J., Mirza, O., Hudson, J. M., Armstrong, F. A., Rothery, R. A., Weiner, J. H., Cecchini, G. 2006; 281 (16): 11357-11365

    Abstract

    The Escherichia coli complex II homologues succinate:ubiquinone oxidoreductase (SQR, SdhCDAB) and menaquinol:fumarate oxidoreductase (QFR, FrdABCD) have remarkable structural homology at their dicarboxylate binding sites. Although both SQR and QFR can catalyze the interconversion of fumarate and succinate, QFR is a much better fumarate reductase, and SQR is a better succinate oxidase. An exception to the conservation of amino acids near the dicarboxylate binding sites of the two enzymes is that there is a Glu (FrdA Glu-49) near the covalently bound FAD cofactor in most QFRs, which is replaced with a Gln (SdhA Gln-50) in SQRs. The role of the amino acid side chain in enzymes with Glu/Gln/Ala substitutions at FrdA Glu-49 and SdhA Gln-50 has been investigated in this study. The data demonstrate that the mutant enzymes with Ala substitutions in either QFR or SQR remain functionally similar to their wild type counterparts. There were, however, dramatic changes in the catalytic properties when Glu and Gln were exchanged for each other in QFR and SQR. The data show that QFR and SQR enzymes are more efficient succinate oxidases when Gln is in the target position and a better fumarate reductase when Glu is present. Overall, structural and catalytic analyses of the FrdA E49Q and SdhA Q50E mutants suggest that coulombic effects and the electronic state of the FAD are critical in dictating the preferred directionality of the succinate/fumarate interconversions catalyzed by the complex II superfamily.

    View details for DOI 10.1074/jbc.M512544200

    View details for Web of Science ID 000236822200078

    View details for PubMedID 16484232

  • Electron transfer and catalytic control by the iron-sulfur clusters in a respiratory enzyme, E. coli fumarate reductase JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Hudson, J. M., Heffron, K., Kotlyar, V., Sher, Y., Maklashina, E., Cecchini, G., Armstrong, F. A. 2005; 127 (19): 6977-6989

    Abstract

    Factors governing the efficacy of long-range electron relays in enzymes have been examined using protein film voltammetry in conjunction with site-directed mutagenesis. Investigations of the fumarate reductase from Escherichia coli, in which three Fe-S clusters relay electrons over more than 30 A, lead to the conclusion that varying the medial [4Fe-4S] cluster potential over a 100 mV range does not have a significant effect on the inherent kinetics of electron transfer to and from the active-site flavin. The results support a proposal that the reduction potential of an individual electron relay site in a multicentered enzyme is not a strong determinant of activity; instead, as deduced from the potential dependence of catalytic electron transfer, electron flow through the intramolecular relay is rapid and reversible, and even uphill steps do not limit the catalytic rate.

    View details for DOI 10.1021/ja043404q

    View details for Web of Science ID 000229085200032

    View details for PubMedID 15884941

  • Effect of anoxia/reperfusion on the reversible active/de-active transition of NADH-ubiquinone oxidoreductase (complex I) in rat heart BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS Maklashina, E., Sher, Y., Zhou, H. Z., Gray, M. O., Karliner, J. S., Cecchini, G. 2002; 1556 (1): 6-12

    Abstract

    The multi-subunit mammalian NADH-ubiquinone oxidoreductase (complex I) is part of the mitochondrial electron transport chain and physiologically serves to reduce ubiquinone with NADH as the electron donor. The three-dimensional structure of this enzyme complex remains to be elucidated and also little is known about the physiological regulation of complex I. The enzyme complex in vitro is known to exist as a mixture of active (A) and de-active (D) forms [Biochim. Biophys. Acta 1364 (1998) 169]. Studies are reported here examining the effect of anoxia and reperfusion on the A/D-equilibrium of complex I in rat hearts ex vivo. Complex I from the freshly isolated rat heart or after prolonged (1 h) normoxic perfusion exists in almost fully active form (87+/-2%). Either 30 min of nitrogen perfusion or global ischemia decreases the portion of active form of complex I to 40+/-2%. Upon re-oxygenation of cardiac tissue, complex I is converted back predominantly to the active form (80-85%). Abrupt alternation of anoxic and normoxic perfusion allows cycling between the two states of the enzyme. The possible role in the physiological regulation of complex I activity is discussed.

    View details for Web of Science ID 000178384600002

    View details for PubMedID 12351213