Acetylation turns leucine into a drug by membrane transporter switching

Churchill, Grant C.; Strupp, Michael; Factor, Cailley; Bremova-Ertl, Tatiana; Factor, Mallory; Patterson, Marc C.; Platt, Frances M.; Galione, Antony

doi:10.1038/s41598-021-95255-5

Cited by 19 publications

(11 citation statements)

References 73 publications

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“…Bei anderen Ataxien zeigte sich aber kein Effekt [59]. Schließlich konnte der Wirkmechanismus näher aufgeklärt werden, bei dem die Acetyl-Gruppe ein wesentlicher Faktor für den transmembranösen Transfer über Monocarboxylat-Transporter mit hoher Kapazität ist [60]. Literatur…”

Section: Therapeutische Möglichkeiten Bei Ausgewählten Ursachen Eines...unclassified

Zerebellärer Schwindel, was steckt dahinter?

Feil¹,

Rattay²,

Adeyemi³

et al. 2023

Nervenheilkunde

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ZUSAMMENFASSUNGSchwindel und Gleichgewichtsstörungen umfassen ein multisensorisches und interdisziplinäres Syndrom unterschiedlicher Ätiologie und Pathogenese, wobei beim zerebellären Schwindel die Beschwerden durch die vestibulo-zerebellären, vestibulo-spinalen oder zerebellären Systeme verursacht werden. Der Begriff des zerebellären Schwindels umfasst eine heterogene Gruppe von Störungen mit klinischen Anzeichen einer Kleinhirnfunktionsstörung. Bei rund 10% der Patienten in einer Spezialambulanz für Schwindel und Gleichgewichtsstörungen ist der zerebelläre Schwindel ursächlich für die Vorstellung. Nach zeitlichem Verlauf können 3 Typen unterschieden werden: dauerhafte Beschwerden, wiederkehrende Episoden mit Schwindel und Gleichgewichtsstörungen und ein akutes Auftreten der Beschwerden. Die häufigsten Diagnosen waren: degenerative Erkrankungen; hereditäre Formen und erworbenen Formen 81 % der Patienten mit einem zerebellären Schwindel leiden an dauerhaften, persistierenden Schwindelbeschwerden, 31 % an Schwindelattacken und 21 % sowohl an dauerhaften Beschwerden als auch an Attacken, während typische klinische zerebelläre Zeichen, u. a. Gang- und Extremitätenataxien oder eine Dysarthrie seltener festgestellt wurden. Schlüssel zur Diagnose sind eine dezidierte, zielgerichtete Anamnese sowie eine gründliche klinische Untersuchung mit besonderem Augenmerk der Okulomotorik. Hinsichtlich der Untersuchung der Okulomotorik zeigten sich am häufigsten eine sakkadierte Blickfolge, ein Blickrichtungsnystagmus, Provokationsnystagmus, Reboundnystagmus, ein zentraler Fixationsnystagmus, am häufigsten der DBN sowie Sakkadenstörungen und einer Divergenzinsuffizienz. Die Untersuchung der Okulomotorik ist somit sehr sensitiv, um die Diagnose zu unterstützen, jedoch nicht spezifisch in der Unterscheidung verschiedener Krankheitsätiologien. Apparative Untersuchungen mittels Posturografie und einer standardisierten Ganganalyse können die Diagnosestellung unterstützen und zur Abschätzung des Sturzrisikos sowie zur Quantifizierung des Verlaufs und möglicher symptomatischer Behandlungseffekte beitragen. Patienten mit zerebellärem Schwindel sollten eine multimodale Behandlung erhalten.

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Section: Therapeutische Möglichkeiten Bei Ausgewählten Ursachen Eines...unclassified

Zerebellärer Schwindel, was steckt dahinter?

Feil¹,

Rattay²,

Adeyemi³

et al. 2023

Nervenheilkunde

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“…Most eukaryotic proteins are acetylated, and free Acetyl-Leucine in humans is thought to primarily derive from these post-translational modifications [ 41 , 42 ], potentially indicating a higher rate of protein degradation among the High-responders, but direct synthesis by Leucine N-AcetylTransferase [ 43 ] or microbial production [ 44 ] is also possible. Studies have shown that N-Acetyl-Leucine is more rapidly taken up by cells, acting as a natural pro-drug to regenerate Leucine intracellularly [ 45 ] and potentially impacting mTOR signaling. Furthermore, the acetylation of Leucine switches its import from the L-type amino acid transporter (LAT1) to the organic anion transporters (OAT1 and OAT3).…”

Section: Discussionmentioning

confidence: 99%

Urine Metabolome Dynamics Discriminate Influenza Vaccination Response

Rodrick¹,

Siu²,

Carlock

et al. 2023

Viruses

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Influenza represents a major and ongoing public health hazard. Current collaborative efforts are aimed toward creating a universal flu vaccine with the goals of both improving responses to vaccination and increasing the breadth of protection against multiple strains and clades from a single vaccine. As an intermediate step toward these goals, the current work is focused on evaluating the systemic host response to vaccination in both normal and high-risk populations, such as the obese and geriatric populations, which have been linked to poor responses to vaccination. We therefore employed a metabolomics approach using a time-course (n = 5 time points) of the response to human vaccination against influenza from the time before vaccination (pre) to 90 days following vaccination. We analyzed the urinary profiles of a cohort of subjects (n = 179) designed to evenly sample across age, sex, BMI, and other demographic factors, stratifying their responses to vaccination as “High”, “Low”, or “None” based on the seroconversion measured by hemagglutination inhibition assay (HAI) from plasma samples at day 28 post-vaccination. Overall, we putatively identified 15,903 distinct, named, small-molecule structures (4473 at 10% FDR) among the 895 samples analyzed, with the aim of identifying metabolite correlates of the vaccine response, as well as prognostic and diagnostic markers from the periods before and after vaccination, respectively. Notably, we found that the metabolic profiles could unbiasedly separate the high-risk High-responders from the high-risk None-responders (obese/geriatric) within 3 days post-vaccination. The purine metabolites Guanine and Hypoxanthine were negatively associated with high seroconversion (p = 0.0032, p < 0.0001, respectively), while Acetyl-Leucine and 5-Aminovaleric acid were positively associated. Further changes in Cystine, Glutamic acid, Kynurenine and other metabolites implicated early oxidative stress (3 days) after vaccination as a hallmark of the High-responders. Ongoing efforts are aimed toward validating these putative markers using a ferret model of influenza infection, as well as an independent cohort of human seasonal vaccination and human challenge studies with live virus.

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“…To date mechanism and site of action of AL still remain unclear. As was recently shown by physicochemical study acetylation of leucine seems to be a crucial factor so that it can be transported into cells including neurons at a very high rate [ 14 ]. An electrophysiological animal study after unilateral peripheral deafferentation in guinea pigs suggested that AL influences the activity of central vestibular nuclei neurons by influencing the channel activity and thereby restoring the membrane potential of depolarized or hyperpolarized vestibular neurons towards normal values [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Acetyl-dl-leucine in cerebellar ataxia ([18F]-FDG-PET study): how does a cerebellar disorder influence cortical sensorimotor networks?

et al. 2022

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Objective The aim of the study was to deepen our insights into central compensatory processes of brain networks in patients with cerebellar ataxia (CA) before and with treatment with acetyl-dl-leucine (AL) by means of resting-state [18F]-FDG-PET brain imaging. Methods Retrospective analyses of [18F]-FDG-PET data in 22 patients with CA (with vestibular and ocular motor disturbances) of different etiologies who were scanned before (PET A) and on AL treatment (PET B). Group subtraction analyses, e.g., for responders and non-responders, comparisons with healthy controls and correlation analyses of regional cerebral glucose metabolism (rCGM) with symptom duration, ataxia (SARA) and quality of life (QoL) scores were calculated. Results Prior to treatment rCGM was consistently downregulated at the cerebellar level and increased in multisensory cortical areas, e.g., somatosensory, primary and secondary visual (including V5, precuneus), secondary vestibular (temporal gyrus, anterior insula), and premotor/supplementary motor areas. With AL (PET B vs. A) cerebellar hypometabolism was deepened and sensorimotor hypermetabolism increased only in responders with clinical benefit, but not for the non-responders and the whole CA group. A positive correlation of ataxia improvement with rCGM was found in visual and vestibular cortices, a negative correlation in cerebellar and brainstem areas. QoL showed a positive correlation with rCGM in the cerebellum and symptom duration in premotor and somatosensory areas. Conclusions Central compensatory processes in CA mainly involve multisensory visual, vestibular, and somatosensory networks as well as premotor/primary motor areas at the cortical level. The enhanced divergence of cortical sensorimotor up- and cerebellar downregulation with AL in responders could reflect amplification of inhibitory cerebellar mechanisms.

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Acetylation turns leucine into a drug by membrane transporter switching

Cited by 19 publications

References 73 publications

Zerebellärer Schwindel, was steckt dahinter?

Zerebellärer Schwindel, was steckt dahinter?

Urine Metabolome Dynamics Discriminate Influenza Vaccination Response

Acetyl-dl-leucine in cerebellar ataxia ([18F]-FDG-PET study): how does a cerebellar disorder influence cortical sensorimotor networks?

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