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Phosphorylation of 5-LOX: The Potential Set-point of Inflammation

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Abstract

Inflammation secondary to tissue injuries serves as a double-edged sword that determines the prognosis of tissue repair. As one of the most important enzymes controlling the inflammation process by producing leukotrienes, 5-lipoxygenase (5-LOX, also called 5-LO) has been one of the therapeutic targets in regulating inflammation for a long time. Although a large number of 5-LOX inhibitors have been explored, only a few of them can be applied clinically. Surprisingly, phosphorylation of 5-LOX reveals great significance in regulating the subcellular localization of 5-LOX, which has proven to be an important mechanism underlying the enzymatic activities of 5-LOX. There are at least three phosphorylation sites in 5-LOX jointly to determine the final inflammatory outcomes, and adjustment of phosphorylation of 5-LOX at different phosphorylation sites brings hope to provide an unrecognized means to regulate inflammation. The present review intends to shed more lights into the set-point-like mechanisms of phosphorylation of 5-LOX and its possible clinical application by summarizing the biological properties of 5-LOX, the relationship of 5-LOX with neurodegenerative diseases and brain injuries, the phosphorylation of 5-LOX at different sites, the regulatory effects and mechanisms of phosphorylated 5-LOX upon inflammation, as well as the potential anti-inflammatory application through balancing the phosphorylation-depended set-point.

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Abbreviations

FDA:

Food and Drug Administration

CNS:

Central nervous systems

AA:

Arachidonic acid

FLAP:

5-Lipoxygenase-activating protein

LOX:

Lipoxygenase

LT:

Leukotriene

cPLA2:

Cytosolic phospholipase A2

LTA4:

Leukotriene A4

LTB4:

Leukotriene B4

LTC4:

Leukotriene C4

LTD4:

Leukotriene D4

iNOS:

Inducible nitric oxide synthase

PTM:

Post-translational modification

TBI:

Traumatic brain injury

AD:

Alzheimer’s disease

Aβ:

Amyloid beta

NFT:

Neurofibrillary tangles

NSC:

Neural stem cell

CLP:

Coactosin-like protein

BMMC:

Mouse bone marrow-derived mast cells

PKA:

Protein kinase A

CaMKII:

Ca2 + /calmodulin-dependent kinase

MAPKAPK:

Mitogen-activated protein kinase-activated protein kinase

MAP:

Mitogen-activated protein

MK:

Mitogen kinase (AP kinase)

COX:

Cyclooxygenase

cPLA2:

Cytosolic phospholipase A2

PG:

Prostaglandin

PMNL:

Polymorphonuclear leukocyte

15-epi- LXA4:

15-Epi-lipoxin A4

ATP:

Adenosine triphosphate

15R-HETE:

(15R)-15-hydroxy-5,8,11-cis-13-trans-eicosa-tetraenoic acid

5-H(p)ETE:

5S-hydro(pero)xy-6,8,11,14(E,Z,Z,Z)-eicosatetraenoic acid

S271:

Serine 271

S523:

Serine 523

S663:

Serine 663

p38:

P38 MAP kinase

ERK:

Extracellular signal-regulated kinase

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Funding

This study was supported by Scientific research project of Guangdong administration of traditional Chinese medicine Fund in China (20191087) and College Students’ Innovation and Entrepreneurship Projects (CX17038, CX18036, CX20139).

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Authors and Affiliations

  1. Department of Physiology, Basic Medical School, Jinan University, Huangpu Avenue 601, Tianhe District, Guangzhou, Guangdong Province, China

    Zonglin He, Di Tao, Jiaming Xiong, Fangfang Lou, Jiayuan Zhang, Jinxia Chen, Weixi Dai, Jing Sun & Yuechun Wang

  2. Faculty of Medicine, International school, Jinan University, Huangpu Avenue 601, Tianhe District, Guangzhou, Guangdong Province, China

    Zonglin He, Di Tao & Weixi Dai

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  1. Zonglin He
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YW is responsible for the conception design and organizational structure for the whole paper. ZH and DT retrieved and organized the literature, and amended the article; JX drew most of the figures, and drafted the article; The other people took part in the literature collection and paper revision. All authors have contributed significantly, and all authors have approved the final version of the manuscript.

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He, Z., Tao, D., Xiong, J. et al. Phosphorylation of 5-LOX: The Potential Set-point of Inflammation. Neurochem Res 45, 2245–2257 (2020). https://doi.org/10.1007/s11064-020-03090-3

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