Leukotriene A4 Hydrolase – An Evolving Therapeutic Target

Shim, Y. Michael; Paige, Mikell

doi:10.5772/25595

Cited by 2 publications

(3 citation statements)

References 172 publications

(120 reference statements)

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“…Since PGP interaction with LTA 4 H is not completely characterized biochemically, our study is mainly focused on the AP activity of LTA 4 H in the presence of 4MDM. In addition to PGP, dynorphin and enkephalin are peptide-based substrates for the LTA 4 H AP activity 9 – 12 . As reported by Orning and co-workers, LTA 4 H hydrolyzes tripeptides containing an N-terminal arginine more efficiently than other peptide substrates such as dipeptides, tetrapeptides, pentapeptides, and tripeptides with non-arginine N-termini 22 .…”

Section: Introductionmentioning

confidence: 99%

Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation

Lee

Ali

Lee

et al. 2022

Sci Rep

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The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTA4H modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTA4H AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTA4H by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTA4H.

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Section: Introductionmentioning

confidence: 99%

Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation

Lee

Ali

Lee

et al. 2022

Sci Rep

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“…In the periphery LTA4H plays a proinflammatory role (18,63). To understand whether LTA4H inhibition could affect cell types important for inflammation in the brain, microglia activation was quantified using the histological markers ionized calcium binding adaptor molecule 1 (Iba1) and CD68.…”

Section: Lta4h Inhibition Targets Pathways Responsible For Synaptic O...mentioning

confidence: 99%

“…LTs are a group of biologically active lipid mediators (LTA4, LTB4, LTC4, LTD4, and LTE4), which are secreted from multiple cell types and play a critical role in recruiting leukocytes and other immune cells to sites of inflammation in the periphery (18). Cysteinyl LTs (Cys-LTs), LTC4, LTD4, and LTE4 have been shown to influence CNS diseases including traumatic brain injury, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, epilepsy, Huntington's disease, depression, and gulf war illness (19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function

Adams,

Rege,

Liu

et al. 2023

Sci. Adv.

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Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function. In addition, LTA4H plasma levels are increased in both aging and Alzheimer’s disease and correlated with cognitive impairment. These results identify a role for LTA4H in the brain, and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases.

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Leukotriene A4 Hydrolase – An Evolving Therapeutic Target

Cited by 2 publications

References 172 publications

Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation

Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function

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