Chiral Posttranslational Modification to Lysine epsilon-Amino Groups

The sophistication of proteomic analysis has revealed that protein lysine residues are posttranslationally modified by a variety of acyl groups. Protein lysine acetylation regulates metabolism, gene expression, and microtubule formation and has been extensively studied; however, the understanding of the biological significance of other acyl posttranslational modifications (PTMs) is still in its infancy. The acylation of lysine residues is either mediated by acyltransferase ‘writer’ enzymes or through non-enzymatic mechanisms and hydrolase enzymes, termed ‘erasers’, cleave various acyl PTMs to reverse the modified state. We have studied the human lysine deacylase enzymes, comprising the 11 Zn2+-dependent histone deacetylases (HDACs) and the 7 NAD+-consuming sirtuins (SIRTs), over the last decade. We have thus developed selective inhibitors and molecular probes as well as studied the acyl substrate scope of each enzyme using chemically synthesized peptide substrates and photo-crosslinking probes. Recently, we have turned our attention to lysine PTMs containing a stereogenic center, such as -N--hydroxybutyryllysine (Kbhb) and -N-lactyllysine (Kla), that each comprise a pair of mirror image stereoisomers. Both modifications are found on histones, where they affect gene transcription in response to specific metabolic states, and they are found on cytosolic and mitochondrial enzymes involved in fatty acid oxidation (Kbhb) and glycolysis (Kla), respectively. Thus, chiral modifications to lysine side chains give rise to two distinct diastereomeric products, with separate metabolic origins and potentially different activities exhibited by writer and eraser enzymes. Lysine L-lactylation derives from L-lactate, a major energy carrier produced from pyruvate after glycolysis, and it is highly induced by metabolic states such as the Warburg effect. L-Lactate can possibly be activated by acyl-coenzyme A (CoA) synthetases and transferred to lysine residues by histone acetyltransferases such as p300. D-Lactylation, on the other hand, arises primarily from a non-enzymatic reaction with D-lactylglutathione, an intermediate in the glyoxalase pathway. In addition to their distinct origin, we found that both K(L-la) and K(D-la) modifications are erased by HDACs with different catalytic efficiencies. Also, K(L-bhb) and K(D-bhb) arise from different metabolites but depend on interconnected metabolic pathways, while the two stereoisomers of -N-3-hydroxy-3-methylglutaryllysine (Khmg) derive from a single precursor that may then be regulated differently by eraser enzymes. Distinguishing between the individual stereoisomers of PTMs is therefore of crucial importance. In the present Account, we will (1) revisit the long-standing evidence for distinct production and dynamics of enantiomeric forms of chiral metabolites that serve as epsilon-N-acyllysine PTMs and (2) highlight the outstanding questions that arise from the recent literature on chiral lysine PTMs resulting from these metabolites

Development and mechanistic investigation of the dehydrogenation of alcohols with an iron(iii) salen catalyst

The iron(iii) salen complex (R,R)-N,N′-bis(salicylidene)-1,2-cyclohexanediamineiron(iii) chloride has been developed as a catalyst for the acceptorless dehydrogenation of alcohols. The complex catalyzes the direct synthesis of imines in good yields from different primary alcohols and amines with the liberation of hydrogen gas. The mechanism has been investigated experimentally with labelled substrates and theoretically with density functional theory calculations. In contrast to the corresponding manganese(iii) salen-catalyzed dehydrogenation, it has not been possible to identify a homogeneous catalytic pathway with the iron complex. Instead, poisoning experiments with trimethylphosphine and mercury indicated that the catalytically active species are heterogeneous small iron particles.</p

Rearrangement of Thiodepsipeptides by S–N Acyl Shift Delivers Homodetic Autoinducing Peptides

Group behavior in many bacteria relies on chemically induced communication called quorum sensing (QS), which plays important roles in regulation of colonization, biofilm formation, and virulence. In Gram-positive bacteria, QS is often mediated by cyclic ribosomally synthesized and posttranslationally modified peptides (RiPPs). In staphylococci for example, most of these so-called autoinducing peptides (AIPs) contain a conserved thiolactone functionality, which has been predicted to constitute a structural feature of AIPs from other species as well. Here, we show that pentameric AIPs from Lactobacillus plantarum, Clostridium perfringens, and Listeria monocytogenes that were previously presumed to be thiolactone-containing structures readily rearrange to become homodetic cyclopeptides. This finding has implications for the developing understanding of the cross-species and cross-genus communication of bacteria and may help guide the discovery of peptide ligands to perturb their function

Vitamin C Acutely Affects Brain Perfusion and Mastication-Induced Perfusion Asymmetry in the Principal Trigeminal Nucleus

Prolonged mastication may induce an asymmetric modification of the local perfusion of the trigeminal principal nucleus. The aim of the present study was to evaluate the possible influence of vitamin C (vit. C) on such effect. Four groups of healthy volunteers underwent arterial spin labeling magnetic resonance imaging (ASL-MRI) to evaluate the local perfusion of the trigeminal nuclei after a vit. C-enriched lunch or a control lunch. Two ASL-MRI scans were acquired, respectively, before and after a 1 h-long masticating exercise or a 1 h long resting period. The results showed (i) an increased global perfusion of the brain in the vit. C-enriched lunch groups, (ii) an increased local perfusion of the right principal trigeminal nucleus (Vp) due to mastication, and (iii) a reduction of the rightward asymmetry of the Vp perfusion, due to mastication, after the vit C-enriched meal compared to the control meal. These results confirmed a long-lasting effect of prolonged mastication on Vp perfusion and also suggest a possible effect of vit. C on cerebral vascular tone regulation. Moreover, the data strongly draw attention on the side-to-side relation in Vp perfusion as a possible physiological parameter to be considered to understand the origin of pathological conditions like migraine

ECG analysis in patients with acute coronary syndrome undergoing invasive management: rationale and design of the electrocardiography sub-study of the MATRIX trial.

BACKGROUND The twelve‑lead electrocardiogram (ECG) has become an essential tool for the diagnosis, risk stratification, and management of patients with acute coronary syndromes (ACS). However, several areas of residual controversies or gaps in evidence exist. Among them, P-wave abnormalities identifying atrial ischemia/infarction are largely neglected in clinical practice, and their diagnostic and prognostic implications remain elusive; the value of ECG to identify the culprit lesion has been investigated, but validated criteria indicating the presence of coronary occlusion in patients without ST-elevation are lacking; finally, which criteria among the multiple proposed, better define pathological Q-waves or success of revascularisation deserve further investigations. METHODS The Minimizing Adverse hemorrhagic events via TRansradial access site and systemic Implementation of AngioX (MATRIX) trial was designed to test the impact of bleeding avoidance strategies on ischemic and bleeding outcomes across the whole spectrum of patients with ACS receiving invasive management. The ECG-MATRIX is a pre-specified sub-study of the MATRIX programme which aims at analyzing the clinical value of ECG metrics in 4516 ACS patients (with and without ST-segment elevation in 2212 and 2304 cases, respectively) with matched pre and post-treatment ECGs. CONCLUSIONS This study represents a unique opportunity to further investigate the role of ECGs in the diagnosis and risk stratification of ACS patients with or without ST-segment deviation, as well as to assess whether the radial approach and bivalirudin may affect post-treatment ECG metrics and patterns in a large contemporary ACS population

Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines

BACKGROUND: We aimed to examine clinical features, and outcomes of consecutive molecularly characterized patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy. METHODS: A retrospective, longitudinal multicenter cohort of consecutive children and adults with a genetic diagnosis of Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy between 2002 and 2019 was assembled. We defined a priori 3 different patterns of left ventricular remodeling during follow-up: (1) an increase in ≥15% of the maximal left ventricular wall thickness (MLVWT), both in mm and z-score (progression); (2) a reduction ≥15% of the MLVWT, both in mm and z-score (absolute regression); (3) a reduction ≥15% of the MLVWT z-score with a stable MLVWT in mm (relative regression). The primary study end point was a composite of cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator-shock. RESULTS: The cohort comprised 42 patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy, with a median age at diagnosis of 3.5 (interquartile range, 0.2-12.3) years. Freedom from primary end point was 92.7% (95% CI, 84.7%-100%) 1 year after presentation and 80.9% (95% CI, 70.1%-90.7%) at 5 years. Patients with MLVWT z-score >13.7 showed reduced survival compared with those with <13.7. During a median follow-up of 3.7 years (interquartile range, 2.6-7.9), absolute regression was the most common type of left ventricular remodeling (n=9, 31%), followed by progression (n=6, 21%), and relative regression (n=6, 21%). CONCLUSIONS: These findings provide insights into the natural history of left ventricular hypertrophy, and can help inform clinicians regarding risk stratification and clinical outcomes in patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy

Double-outlet left ventricle: single-center experience and literature review

Double-outlet left ventricle (DOLV) is an abnormal ventriculo-arterial connection characterized by origin of both great arteries, or more than 50% of each arterial root, from the morphological left ventricle. The aim of our paper is to describe the anatomic, echocardiographic, and multi-modality imaging characteristics of DOLV and associated malformations, and to assess its surgical outcomes. Methods: From 2011 to 2022, we retrospectively reviewed case records, intra-operatory reports and follow-up data of patients diagnosed with DOLV at Bambino Gesu Children’s Hospital. A systematic search was developed in MEDLINE, EMBASE and Web of Science databases, to identify original reports between January 1, 1975 and May 30, 2022, assessing the morphology and surgical outcomes of DOLV. Retrospective cohort studies, cross-sectional and case series were included in the analysis. Single case reports and reviews were excluded. Results: At our center, four cases of DOLV were identified. Patient 1 was diagnosed with (S,D,D) DOLV and hypoplastic right ventricle. The aorta overrode a large, doubly-committed VSD with absence of infundibular septum. A tenuous mitro-aortic discontinuity and a well-developed subpulmonary conus were present. Associated abnormalities included crossed pulmonary arteries and two adjacent, side-by-side coronary ostia, located in the anterior facing sinus, which gave origin to the left anterior descending (LAD) and the right coronary artery (RCA). Left circumflex artery (LCx) had a retro-aortic course and originated from the RCA. After pulmonary artery banding, Damus-Kaye-Stansel and Glenn intervention were proposed as first-stage of univentricular palliation. Patient 2 and 3 were diagnosed with (S,D,D) DOLV, subaortic VSD and pulmonary stenosis. Patient 2 underwent Rastelli operation and no anatomic detail were available. Patient 3 showed absence of the infundibular septum and mitro-pulmonary continuity, whereas subaortic conus was well developed. Anomalous origin of the LCx, originating from the posterior facing sinus with retro-aortic course was present. Rastelli procedure was performed to reconstruct right ventricular outflow tract. LCA and RCA were respectively caudal to subvalvular and supravalvular segments of the RV-to-PA conduit. After a 6-years follow-up, severe stenosis of the RV-to-PA conduit was present, nevertheless percutaneous conduit dilatation was contraindicated, due to coronary abnormality, and an aortic homograft was implanted Patient 4 was diagnosed with (S,D,L) DOLV with subaortic VSD and mitro-pulmonary fibrous continuity. A large subaortic conus was present. Reparation à l’etage ventriculaire was performed to reconstruct RVOT. Follow-up MRI at 8 years showed severe pulmonary artery regurgitation with mild RV dilatation (indexed volume 99mL/m2) and normal RV ejection fraction (54 %) Systematic review:Through our systematic research strategy we scrutinized 96 records for inclusion criteria (Figure 4). After systematic evaluation, a total of 9 reports fulfilled eligibility criteria and were included in our study. Morphological findings and surgical outcomes are summarized in Table 1. Among 191 cases of DOLV included, the most common subtypes of VSD were subaortic (128/191), subpulmonary (23/191) or doubly committed (14/191) (Figure 5). d-transposition of the aorta was present in 117/191 (61%) cases, whereas l-transposition was reported in 63/191 (32%) (Figure 6