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Electron Shuttling in Parkinson's Disease Elucidated by Microbial Fuel Cells.
The paper I'll discuss in this post is this one: Deciphering Electron-Shuttling Characteristics of Parkinson’s Disease Medicines via Bioenergy Extraction in Microbial Fuel Cells (Chen et al, Industrial & Engineering Chemistry Research 2020 59 (39), 17124-17136.
Since my regular journal reading list - the reading list for pleasure, as opposed for my paid work - often includes journals focusing on issues relating to energy and the environment, I often come across papers relating to microbial fuel cells. I tend not to read these papers in any level of detail, since my main focus is on carbon dioxide issues and high temperature thermal schemes, but my general feeling is that they may prove to be a way to recover some energy in water treatment systems while simultaneously cleaning up the water.
The current issue of Industrial & Engineering Chemistry Research is about biomass utilization, a topic which is of very high interest to me, since it is one route - certainly not the only route - to capture of carbon dioxide from the air, a topic which will be of extreme importance in the future given our ongoing failure to do anything even remotely practical to address climate change.
In spite of my low passing interest in microbial fuel cells, this particular article caught my eye because my oldest son, a designer/artist, has an independent interest in neurobiology as it relates to perception and in general, to mood and to consciousness itself. In addition my youngest son's girlfriend is studying neurobiological psychology. Also any paper that intrinsically brings together two very disparate scientific issues is immediately interesting.
From the introductory text:
Due to gradual exhaustion of fossil fuels over the globe, exploring green sustainability and renewable energy applications has become an important issue. In particular, bioenergy could be regenerated without secondary pollution and thus be considered as the most environmentally friendly renewable energy in the world. Among them, microbial fuel cells (MFCs) as bioelectrochemical systems utilize electroactive microbes to directly oxidize organics, converting chemical energy to be bioelectricity. In addition, provided that specific microbes were selected for bioelectric generation in MFCs, exogenous supplementation of energy nutrients or electron shuttles (ESs) could significantly enhance electron-transport phenomena, leading to remarkable rises in bioelectricity generation.(1) To improve the power-generating efficiency, augmentation of exogenous ESs as “electrochemical catalysts” to MFCs was found to be very electroactive to promote electron transfer efficiency for power generation.(2) Owing to electron-shuttling characteristics, phenolic derivatives could form stable “radical-resonant” intermediates to promote the electron transfer for redox reaction(s). Such stable and reversible transferring capabilities could take place via electron/radical delocalization within the chemical structure through the resonance effects.(3) As a matter of fact, such a resonance effect could stably take place at the benzene ring of the aromatic structure. That is, the benzene ring of the aromatic structure may be one of the necessary criteria to initiate the electron-shuttling capability to be effectively expressed. In addition, regarding the electrochemical characterization of different functional group(s) (e.g., hydroxyl (?OH), amine (?NH2), carboxy (?COOH)) on the benzene ring, as O and N are more electronegative than C, this leads to their strong tendency as antioxidants...
... Moreover, for dihydroxyl (diOH)-bearing aromatics, compared to meta-isomers, ortho- or para-dihydroxyl (diOH) substituent-bearing phenolics possessed more promising electrochemical activities for electron-shuttling.(5,6) For example, the literature(7) further mentioned that accumulation of azo dye-decolorized metabolites (DMs) could catalytically stimulate the efficiency of electron transfer, thereby enhancing the bioelectricity generation of MFCs. However, microbial decolorization of azo dyes would generate aromatic amine (?NH2) intermediates,(8) inevitably leading to possible concerns of secondary pollution to the environment...
...Recently, the study(10) has also evaluated ortho-diOH-substituents (e.g., o-diOH-bearing dopamine (DA) and epinephrine (EP)), showing that such neurotransmitter-related chemicals could significantly mediate electrochemical properties, thereby effectively promoting bioelectricity generation in MFCs. It was also suspected that such electron-mediating capabilities were strongly associated with neurotransmission among neurons, muscle cells, or gland cells. For example, DA is an endogenous hormone and neurotransmitter in the human brain and body. It is released from presynaptic neurons to synaptic cleft and binds to postsynaptic receptors to causes actions of postsynaptic cells, in turn promoting transmission among postsynaptic cells.(11)...
...The major families of drugs to treat PD are dopamine agonists, Levodopa, and monoamine oxidase inhibitors (MAO-B inhibitors).(16,17) They are applied to different nerve conduction or neurotransmitting pathways to reduce symptoms of PD. In fact, as Levodopa and dopamine are electron-shuttling chemicals, it was thus proposed that the involvement or initiation of DA-associated chemicals with high bioelectrochemical-catalyzing activities seemed to be significant for disease medication. That was why this study selected seven representative medicines used in clinical treatment for comparative assessment (Figure 1; Table S1)...
... Moreover, for dihydroxyl (diOH)-bearing aromatics, compared to meta-isomers, ortho- or para-dihydroxyl (diOH) substituent-bearing phenolics possessed more promising electrochemical activities for electron-shuttling.(5,6) For example, the literature(7) further mentioned that accumulation of azo dye-decolorized metabolites (DMs) could catalytically stimulate the efficiency of electron transfer, thereby enhancing the bioelectricity generation of MFCs. However, microbial decolorization of azo dyes would generate aromatic amine (?NH2) intermediates,(8) inevitably leading to possible concerns of secondary pollution to the environment...
...Recently, the study(10) has also evaluated ortho-diOH-substituents (e.g., o-diOH-bearing dopamine (DA) and epinephrine (EP)), showing that such neurotransmitter-related chemicals could significantly mediate electrochemical properties, thereby effectively promoting bioelectricity generation in MFCs. It was also suspected that such electron-mediating capabilities were strongly associated with neurotransmission among neurons, muscle cells, or gland cells. For example, DA is an endogenous hormone and neurotransmitter in the human brain and body. It is released from presynaptic neurons to synaptic cleft and binds to postsynaptic receptors to causes actions of postsynaptic cells, in turn promoting transmission among postsynaptic cells.(11)...
...The major families of drugs to treat PD are dopamine agonists, Levodopa, and monoamine oxidase inhibitors (MAO-B inhibitors).(16,17) They are applied to different nerve conduction or neurotransmitting pathways to reduce symptoms of PD. In fact, as Levodopa and dopamine are electron-shuttling chemicals, it was thus proposed that the involvement or initiation of DA-associated chemicals with high bioelectrochemical-catalyzing activities seemed to be significant for disease medication. That was why this study selected seven representative medicines used in clinical treatment for comparative assessment (Figure 1; Table S1)...
Figure 1:
The caption:
Figure 1. Conceptual schematics of metabolic pathways associated with the treatment of Parkinson’s disease medicines: (a) levodopa (L-DOPA), (b) benserazide (BSZ), (c) entacapone (ETP), (d) rasagiline (RSL), (e) amantadine (AMTD), (f) apomorphine (APO), ropinirole (RPNR), bromocriptine (BM).
I sent my sons and my youngest son's girlfriend the following commentary when I emailed this paper to them:
In figure one, the molecule at the top, bromocriptine, labeled "BM," the lower fused ring system is bromolysergic acid, the upper ring system is actually a peptoid - a system that has a peptide structure that has been slightly modified.
The three amino acids in this interesting ring system are valine and isoleucine and proline. The carboxylic acid in proline has been reduced to an aldehyde and then formed into a structure called a "hemiacetal, connected to an oxygen from an oxidized form of valine, alpha hydroxyvaline, making the valine a "aminal." These types of lysergic acid/peptoid structures are very common in the ergot alkaloids, from which several major neuroactive, including neuromuscular active, drugs have been developed, including ergotamine, and methasergide for chronic headaches, ergonovine and methergine to induce labor, and of course, the chemically brominated bromocriptine, utilized in parkinson's.
LSD, and a few other hallucinogenic molecules are also derivatives of lysergic acid, of course.
The point is that all of these molecules act on neurotransmitters.
The three amino acids in this interesting ring system are valine and isoleucine and proline. The carboxylic acid in proline has been reduced to an aldehyde and then formed into a structure called a "hemiacetal, connected to an oxygen from an oxidized form of valine, alpha hydroxyvaline, making the valine a "aminal." These types of lysergic acid/peptoid structures are very common in the ergot alkaloids, from which several major neuroactive, including neuromuscular active, drugs have been developed, including ergotamine, and methasergide for chronic headaches, ergonovine and methergine to induce labor, and of course, the chemically brominated bromocriptine, utilized in parkinson's.
LSD, and a few other hallucinogenic molecules are also derivatives of lysergic acid, of course.
The point is that all of these molecules act on neurotransmitters.
The microbial fuel cells utilized an electroactive organism, Aeromonas hydrophilia, which was originally obtained from a river in Taiwan. It apparently has been investigated for it's ability to decolorize waste water from dyeing plants in the textile industry.
Some more text this from the main body of the paper:
Among PD-associated medicines, both DA and EP contained ortho-dihydroxybenzene structures to show significant potentials to effectively augment bioelectricity formation in MFCs. To extensively confirm such phenomena, this work also quantitatively evaluated such electron-mediating characteristics of candidate chemicals [e.g., 10 typical PD-treating medicines (i.e., dopamine (DA), levodopa (L-DOPA), benserazide (BSZ), rasagiline (RSL), apomorphine (APO), entacapone (ETP), orphenadrine (OPD), amantadine (AMTD), ropinirole (RPNR), bromocriptine mesylate (BM)] which were thus chosen as model medicines for study. That is, such promoting capabilities were suspected to be strongly associated with medication power to treat PD. As DA and EP are crucial neurotransmitting-chemicals in the human brain, this study tended to uncover whether the medicines with redox-mediating capabilities for bioenergy extraction were possibly related to curative power to PD. This study would explore whether they could exhibit such reversible and stable electron-shuttling characteristics to stimulate bioenergy-extracting capabilities.
The authors found that L-Dopa, dopamine, and APO all gave enhanced electrochemical signals in the microbial fuel cell.
Some more figures from the text:
The caption:
Figure 2. Cyclic voltammetric profiles of scan cycle 50 for some neurotransmitters and Parkinson’s medicines (0.3 mM): (a) dopamine (DA), (b) levodopa (L-DOPA), (c) benserazide (BSZ), and (d) apomorphine (APO). (Note that, as BSZ was not so electrochemically sensitive to CV analysis, a higher concentration of 30 mM was chosen for testing.)
The caption:
Figure 4. MS/MS fragment analysis of apomorphine (APO) (a) before (powder) and (b) after (0.3 mM) cyclic voltammetry in treatment of 50 cycles (positive ion (+p); negative ion (?p)).
The authors utilized a high resolution mass spec, a Thermo Q Exactove Plus - an orbitrap mass spec - to study the products of the APO, apomorphine, in the fuel cell.
The caption:
Figure 4. MS/MS fragment analysis of apomorphine (APO) (a) before (powder) and (b) after (0.3 mM) cyclic voltammetry in treatment of 50 cycles (positive ion (+p); negative ion (?p)).
The authors studied the power density of the microbiological fuel cells in the presence of Parkinson's medications. Note that the units give a feel for the required size for these types of devices:
The caption:
Figure 5. Comparison of power-density profiles using 0.3 mM neurotransmitters and Parkinson’s medicines by two separate A. hydrophila NIU01-inoculated microbial fuel cells [blank (BK) was control MFC in the absence of test chemical; abbreviations denoted as benserazide (BSZ), apomorphine (APO), dopamine (DA), levodopa (L-DOPA), orphenadrine (OPD), amantadine (AMTD), and ropinirole (RPNR)].
The authors studied various hydroxybenzenes, a few of which are available from lignins, suggesting that the "black liquor" of paper making, which contains lignins, may be utilized in microbial fuel cell type systems to clean up the black liquor if the base can be neutralized. It should be said that lignins, I believe, will have many future uses in a post dangerous fossil fuel world, should one ever come to exist. I should note in the context of this paper, that one of the trihydroxybenzenes listed here, gallic acid, which can be obtained from wood, is a potential synthetic precursor to the neurologically active hallucinogen mescaline, in six - possibly fewer - steps, the point being that hydroxylated benzenes screw with your nerves. (The street drug known as Ecstasy or "Molly" is also a hydroxybenzene derivative, as is vanilla.)
The caption:
Figure 6. Cyclic voltammetric profiles of some model di- or trihydroxyl-based polyhydroxybenzenes (0.3 mM) at 50 cycles of CV scan: (a) catechol (1,2-DHB), resorcinol (1,3-DHB), and hydroquinone (1,4-DHB); and (b) pyrogallol (1,2,3-THB), phloroglucinol (1,3,5-THB), hydroxyhydroquinone (1,2,4-THB), and gallic acid (GA).
The caption:
Figure 7. Comparative profiles of power-density profiles using 0.3 mM dihydroxyl- or trihydroxyl-based polyhydroxybenzenes by (a) A. hydrophila NIU01-inoculated microbial fuel cells NIU01 and (b) mixed consortia-seeded microbial fuel cells (MFC-A) (blank (BK) denoted the control or test chemical-absent MFC; abbreviations denoted as catechol (1,2-DHB), resorcinol (1,3-DHB), hydroquinone (1,4-DHB), pyrogallol (1,2,3-THB), phloroglucinol (1,3,5-THB), hydroxyhydroquinone (1,2,4-THB), gallic acid (GA)).
This first-attempt study deciphered electrochemical characteristics of PD-associated medicines, implying that APO and BSZ for the medication of PD were strongly related to their redox-mediating capabilities. The most electrochemically promising species APO enhanced the activity of dopamine receptors, significantly augmenting the efficacy of PD medication. In addition, BSZ inhibited L-ADD activity in periphery for PD medication. Other medicines seemed not to be strongly associated with electrochemical activity for PD medication. To suggest feasible phenolics-containing organics as PD medicines, several model polyphenolics were compared for bioenergy-stimulating capabilities. In fact, hydroxyhydroquinone, pyrogallol, and hydroquinine were all electrochemically outstanding ESs (e.g., increased ca. 4–6 fold power generation in MFCs), implying that chemicals with such similar chemical structures should exhibit promising electrochemical characteristics for the medication of PD. In addition, this study also pointed out that MFC modules should be more promising bioelectrochemical devices to directly exhibit not only electrochemical properties but also the biocompatible nature of test chemical(s) for applications in biotechnology. This work also disclosed a guideline to disclose bioelectrochemical characteristics of chemical(s) associated with pharmaceutical capabilities, suggesting bioenergy stimulation as possible electrochemical means to catalyze drug medication.
A brief excerpt of the conclusion:
Regarding bioenergy stimulation, supplementing ortho- and para-polyhydroxybenzene chemicals to MFCs effectively augmented the performance of bioelectricity generation ca. 92–576%. Thus, polyhydroxybenzene-bearing aromatics could express significant electrochemical activity to improve bioelectricity-stimulating efficiency in MFCs. However, augmentation of non-polyphenolics-related chemicals to MFCs could not exhibit appropriate electrochemical characteristics to promote bioelectricity generation. It was suspected that supplementing ortho- or para-polyhydroxybenzene-based medicines (e.g., APO) for curative mediation of PD was very likely due to their bioenergy-stimulating capabilities.
An interesting and different approach to drug screening I think. Whether it would prove superior to other screening tools, I can't say. I haven't worked in neuroactive drug development, except for some very remotely related work on Alzheimer's medications and a few purely analytical programs for drugs utilized in PD.
Have a pleasant Sunday.
2 replies
= new reply since forum marked as read
= new reply since forum marked as read
In my defense, I wrote this post very late at night, when I was supposed to be sleeping, and, in fact, wrote the email to the "kids" at the same time.
Strange things can happen in biological molecules. I have always wanted to understand the biosynthesis of molecules like this, but have never had time to look into it. For a time as a kid, I was a peptide chemist, and so whenever I see complex structures like this, I look for the peptidyl cores. Some retain considerable peptide character, one of my favorites being vancomycin, with chlorinated tyrosines in the core.
I'm sure someone's done a total synthesis, but damn, a bacterium makes that thing effortlessly.
I'll see if any of the "kids" come back with the correction. If any of them have taken organic chemistry, it's probably only my son's girlfriend. My youngest son did work to teach himself organic chemistry during his freshman to sophomore summer internship in France. I'm not quite sure how far he got, but he is thinking of joining a biomaterials lab in graduate school, so I advised him to either take an organic chemistry course or at least review what he learned on his own in France. He's kind of busy right now, in his last semester of undergraduate school.
Thanks very much for the correction.
