Enzymatic Hydrolysis of Long-Chain Alkanoylcholines in Rat Intestinal Loops

Chelminska-Bertilsson, Monika; Edebo, Anders; Thompson, Richard A.; Edebo, L.

doi:10.3109/00365529509096311

Cited by 6 publications

(15 citation statements)

References 16 publications

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“…Apart from these enzymes, more specific serine proteases such as trypsin cleaving proteins at the carboxyl side of the amino acids lysine or arginine, as well as the butyrylcholinesterase (BChE) are involved in the degradation of cationic and ionizable cationic lipids. [ 6a,40 ] The degradation by trypsin has recently been exploited for ionizable cationic lipids based on the amino acids lysine and arginine. [ 5d,6a,40c,41 ] Furthermore, cell membrane bound enzymes seem to contribute to the degradation of biodegradable lipids.…”

Section: Biodegradationmentioning

confidence: 99%

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Jörgensen

Wibel

Bernkop‐Schnürch

2023

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The use of cationic and ionizable cationic lipids in pharmaceutical products, however, is a double-edged sword, as these excipients are of considerable safety concerns. Because of their permanent or pHdependent cationic nature, they perturbate cellular and nuclear membranes, trigger the release of degrading enzymes from lysosomes, cause mitochondrial permeabilization and dysfunction, generate reactive oxygen species (ROS), alter cytoplasmatic enzyme functions, and damage DNA. [3] To address this substantial shortcoming of cationic and ionizable cationic lipids, biodegradable alternatives have been introduced that are rapidly degraded in vivo to preferably endogenous metabolites. The design of such lipids is inspired by natural cationic or ionizable cationic compounds like arginine, lysine or betaine that are generally regarded as safe. Their conjugation to endogenous lipids like fatty acids or cholesterol results in amphiphilic lipids. As ester and amide bonds are cleaved in vivo by numerous enzymes such as lipases, esterases, and proteases, they are the preferred linkages between these natural building blocks.Since the FDA approved ethyl Nα-lauroyl-l-arginate as biodegradable food preservative being effective against a broad range of Gram-positive and Gram-negative bacteria, yeasts, and molds in 2005, [4] the potential use of biodegradable cationic and ionizable cationic lipids as pharmaceutical excipients has been evaluated by numerous research groups. As these excipients exhibit the same properties as their non-biodegradable counterparts but causing relatively low adverse effects, they will likely substitute currently used non-biodegradable lipids in the future. Within this review, we provide an overview on the different types of biodegradable cationic and ionizable cationic lipids, their synthesis and cleavage by endogenous enzymes. Applications in drug delivery systems and as antimicrobial agents are discussed. A guideline on their design and application is provided and an outlook on future developments is given. Building Blocks and Formation of Cationic and Ionizable Cationic LipidsGenerally, biodegradable cationic and ionizable cationic lipids are composed of biocompatible building blocks that are conjugated via a linkage such as an ester or amide bond. [5] Representative building blocks and linkages are depicted in Figure 1. Endogenous enzymes can break these linkages and degrade Cationic and ionizable cationic lipids are broadly applied as auxiliary agents, but their use is associated with adverse effects. If these excipients are rapidly degraded to endogenously occurring metabolites such as amino acids and fatty acids, their toxic potential can be minimized. So far, synthesized and evaluated biodegradable cationic and ionizable cationic lipids already showed promising results in terms of functionality and safety. Within this review, an overview about the different types of such biodegradable lipids, the available building blocks, their synthesis and cleavage by endogenous enzymes is provided. Moreover, ...

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Section: Biodegradationmentioning

confidence: 99%

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Jörgensen

Wibel

Bernkop‐Schnürch

2023

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“…The in vitro hydrolysis studies were complemented with an investigation on the hydrolysis of alkanoylcholines in a biological environment, the rat intestine (5). These studies showed that alkanoylcholines are readily hydrolyzed in vivo and that the rate of hydrolysis decreases with increasing hydrocarbon chain length.…”

mentioning

confidence: 99%

Long-chain alkanoylcholines, a new category of soft antimicrobial agents that are enzymatically degradable

Ahlström

Chelminska-Bertilsson

Thompson

et al. 1995

Antimicrob Agents Chemother

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A new category of amphiphilic hydrolyzable quaternary ammonium compounds with rapid and high levels of antimicrobial activity was studied. The compounds, alkanoylcholines with hydrocarbon chains of 10 to 14 carbon atoms, are hydrolyzed by butyrylcholine esterase, which is present in human serum and mucosal membranes. The hydrolysis products are common components of human metabolism. Alkanoylcholines were tested and found to be active against gram-negative and gram-positive bacteria as well as yeasts. The microbicidal activities of the alkanoylcholines were comparable to the activities of the stable quaternary ammonium compounds of corresponding chain length and increased with an increasing number of carbon atoms. The compounds were also found to be hydrolyzed by enzymes present in certain microorganisms. The degradation was achieved after reaching the microbicidal effect.

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“…Hydrolysis of myristoylcholine by neuromuscular junction BChE is inhibited by the dual acetylcholinesterase/butyrylcholinesterase inhibitor eserine (also known as physostigmine), but with even greater sensitivity than that of acetylcholine . The hydrolysis of multiple long-chain acylcholines species by horse serum BChE has been established. , The eserine-inhibitable hydrolysis of succinylcholine esters and other dicarboxylic acid-choline esters confirms the importance of BChE in inactivating muscle relaxants like succinylcholine …”

Section: Metabolism Of Acylcholinesmentioning

confidence: 85%

“…While the biology of acylcholines is beginning to be understood, aspects of their metabolism and biochemistry have been described. BChE shows hydrolytic activity toward long-chain acylcholines, ,, which might serve to control systemic acylcholine levels (explaining class-level trends observed with disease). Additional evidence can also be observed in the negative correlation between acylcholine levels and BChE activity, which mirrors that of another known substrate of BChE, acyl-ghrelin. , …”

Section: Omic Analyses Expand Endogenous Targets For Bchementioning

confidence: 99%

“…Butyrylcholine is hydrolyzed by human BChE 2 to 3 times more efficiently than acetylcholine, , whereas it is not hydrolyzed by human acetylcholinesterase . Prior to evidence of their presence in biological tissues, long-chain acylcholines were studied as “theoretical” substrates for BChE where the hydrolysis of decanoylcholine, lauroylcholine, and myristoylcholine was demonstrated using BChE present in crude preparations of fluid, mucus, and tissue from intestines . Interestingly, as hinted at in Tables and , so far metabolomics studies have not identified acylcholines with acyl chain lengths between C4 and C16.…”

Section: Metabolism Of Acylcholinesmentioning

confidence: 99%

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Long-Chain Acylcholines Link Butyrylcholinesterase to Regulation of Non-neuronal Cholinergic Signaling

Kinchen¹,

Mohney²,

Pappan³

2021

J. Proteome Res.

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Acylcholines are comprised of an acyl chain esterified to a choline moiety; acetylcholine is the best-characterized member of this class, functioning as a neurotransmitter in the central and peripheral nervous systems as well as an inhibitor of cytokine production by macrophages and other innate immune cells. Acylcholines are metabolized by a class of cholinesterases, including acetylcholinesterase (a specific regulator of acetylcholine levels) and butyrylcholinesterase (BChE, an enigmatic enzyme whose function has not been resolved by genetic knockout models). BChE provides reserve capacity to hydrolyze acetylcholine, but its importance is arguable given acetylcholinesterase is the most catalytically efficient enzyme characterized to date. While known to be substrates of BChE in vitro, endogenous production of long-chain acylcholines is a recent discovery enabled by untargeted metabolomics. Compared to acetylcholine, long-chain acylcholines show greater stability in circulation with homeostatic levels–dictated by synthesis and clearance–suggested to impact cholinergic receptor sensitivity of acetylcholine with varying levels of antagonism. Acylcholines then provide a link between BChE and non-neuronal acetylcholine signaling, filling a gap in understanding around how imbalances between acylcholines and BChE could modulate inflammatory disease, such as the “cytokine storm” identified in severe COVID-19. Areas for further research, development, and clinical testing are outlined.

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Enzymatic Hydrolysis of Long-Chain Alkanoylcholines in Rat Intestinal Loops

Cited by 6 publications

References 16 publications

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Long-chain alkanoylcholines, a new category of soft antimicrobial agents that are enzymatically degradable

Long-Chain Acylcholines Link Butyrylcholinesterase to Regulation of Non-neuronal Cholinergic Signaling

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