Metabolomics and computational analysis of the role of monoamine oxidase activity in delirium and SARS-COV-2 infection

Abstract

Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found significant concentration differences in several amino acids, acylcarnitines and polyamines linking delirium-prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein–protein docking analysis showed that there potentially is strong binding of SARS-CoV-2 spike protein to MAOB. The possibility that SARS-CoV-2 influences MAOB activity leading to the observed neurological and platelet-based complications of SARS-CoV-2 infection requires further investigation.

COVID-19 infection and neurodegeneration: Computational evidence for interactions between the SARS-CoV-2 spike protein and monoamine oxidase enzymes

“…In concluding this section, let us emphasize that the affinity of both SARS-CoV-2 variants towards the MAO isoforms is very much comparable to that for their ACE2 receptor, thus indicating a feasibility and likeliness of the WT/SA∙∙∙MAO A/B complex formation. The latter is especially justified knowing that the structural comparison of the ACE2–spike protein binding region with MAO B resulted in approximately 90% structure overlap, despite only 51% structural similarity with the overall ACE2 structure [36] . Our results demonstrate that this recognition is particularly favourable for SA∙∙∙MAO B, where the calculated binding energy surpasses that of SA∙∙∙ACE2 by –7.9 kcal mol –1 , thus offering an interesting insight and perspective.…”

“…Lastly, we evaluated how the WT/SA∙∙∙MAO complexes impact MAO activity through the affinity for their brain amines. In doing so, we considered phenylethylamine ( PEA ) for both MAO isoforms, in order to place our results in the context of experimental findings by Cuperlovic-Culf, Green and co-workers [36] , and more specific amine neurotransmitters serotonin ( SER ) and dopamine ( DOP ), which are typical substrates for MAO A and MAO B, respectively. The calculated affinities are given in Table 2 and compared to relevant Michaelis-Menten constants, K M .…”

“…Since MAO enzymes are involved in the metabolic clearance and regulation of brain amine levels [27] , [28] , including neurotransmitters dopamine and serotonin, whose even the slightest disparity is strongly linked to the etiology and course of various neurological illnesses [29] , [30] , [31] , such a downregulation and modified MAO activity likely represent incipient stages of neurological disturbances, which are already broadly speculated in the literature [32] , [33] , [34] , [35] . Importantly, a potential relationship between the MAO enzymes and the SARS-CoV-2 infection has recently been proposed by Cuperlovic-Culf, Green and co-workers [36] , who used metabolomic profiling to detect a decrease in the concentration of phenylethylamine ( PEA ) metabolites within the cerebrospinal fluid and blood of COVID-19 related patients relative to healthy individuals, a trend similarly observed with more than 200 other metabolites, involving amino acids and their derivatives [37] . Knowing that MAO B preferentially degrades PEA in the CNS [27] , the authors ascribed this observation to a possible interference of the spike protein with the substrate entrance to the MAO B active site, thus providing a justification to our hypothesis.…”

Delirium and Cognitive Impairment as Predisposing Factors of COVID-19 Infection in Neuropsychiatric Patients: A Narrative Review

“…Thus, the authors hypothesized that the clinical condition observed in both patients was probably associated with a neuroinfection or an autoimmune encephalopathy. Furthermore, Cuperlovic-Culf et al [111] hypothesized a relationship between delirium and SARS-CoV-2 infection via a possible binding of SARS-CoV-2 spike protein to monoamine oxidase B (MAO-B) enzymes, which influences the enzyme activity and possibly leads to many of the observed neurological and platelet-based complications of SARS-CoV-2 infection.…”

Does acute and persistent metabolic dysregulation in COVID-19 point to novel biomarkers and future therapeutic strategies?

“…The earliest reports identified changes in the metabolic pathways for processing lipids, amino acids, and carbohydrates in severely ill COVID-19 patients. More recent studies have begun to associate metabolomics changes with symptoms representing specific organ system failures – for example, the acute delirium and post-recovery mental health issues of the nervous system and disruptions of the digestive system [ 6 , 7 ]. Dysregulation of the kynurenine pathway has been among the most consistent findings as reported in numerous, independent studies [ 5 ].…”