Hydrogen sulfide-induced post-translational modification as a potential drug target

Abstract

Hydrogen sulfide (H₂S) is one of the three known gas signal transducers, and since its potential physiological role was reported, the literature on H₂S has been increasing. H₂S is involved in processes such as vasodilation, neurotransmission, angiogenesis, inflammation, and the prevention of ischemia-reperfusion injury, and its mechanism remains to be further studied. At present, the role of post-translational processing of proteins has been considered as a possible mechanism for the involvement of H₂S in a variety of physiological processes. Current studies have shown that H₂S is involved in S-sulfhydration, phosphorylation, and S-nitrosylation of proteins, etc. This paper focuses on the effects of protein modification involving H₂S on physiological and pathological processes, looking forward to providing guidance for subsequent research.

Keywords: Hydrogen sulfide; Modification; Phosphorylation; S-nitrosylation; S-sulfhydration.

Figure 1

The main way of synthesis and metabolism of H₂S. Endogenous H₂S is mainly produced by three enzyme-catalyzed substrates of CBS, CSE, and 3-MST, and its path mainly includes enzymatic and non-enzymatic degradation. CAT: cysteine aminotransferase; CBS: cystathionine β-synthase; CSE: cystathionine gamma-lyase; DAO: d-amino acid oxidase; 3-MST: 3-mercaptopyruvate sulfurtransferase; PLP: pyridoxal-5-phosphate; SQR: sulfide quinone oxidoreductase system.

Figure 2

The role of different proteins in the cardiovascular system after S-sulfhydration. After protein S-sulfhydration, it exerts anti-oxidative stress in the cardiovascular system, restores ER homeostasis, regulates ion channels, and regulates glucose and lipid metabolism. It plays a role in blood pressure regulation, atherosclerotic plaque formation, and cardiac hypertrophy. CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; CTSS: cathepsin S; ER: endoplasmic reticulum; ERK1/2: extracellular regulated protein kinase 1/2; HuR: human antigen R; IGF1: insulin-like growth factor-1; IGF1R: insulin-like growth factor-1 receptor; Keap-1: Kelch-like ECH-associated protein1; Kir6.1: ATP-sensitive potassium channel 6.1; KLF5: Krüppel-like factor 5; MEK1: mitogen-activated extracellular signal-regulated kinase 1; MuRF1: muscle RING finger-1; Nrf2: nuclear factor E2-related factor 2; PARP-1: poly (ADP-ribose) polymerase-1; PDI: protein disulphide isomerase; PIP2: phosphatidylinositol (4,5)-bisphosphate; PPARγ：peroxisome proliferator-activated receptor γ; PTP1B: protein tyrosine phosphatase 1B; SP1: specific protein-1; TRPV4 and TRPV1: transient receptor potential family member; VEGFR2: vascular endothelial growth factor receptor 2.

Figure 3

S-sulfhydration plays a role in synapses and participates in memory formation. H₂S participates in memory formation through S-sulfhydration of GAPDH, SR, PKA, PKC, and CaMKII, which may all be related to LTP. AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; CBS: cystathionine β-synthase; GluR1: AMPAR subunit; LTP: long-term potentiation; NMDAR: N-methyl-d-aspartate subtype glutamate receptor; PSD95: postsynaptic density 95; Siah: E3 ubiquitin protein ligase; SR: serine racemase.

Figure 4

The role of S-sulfhydration in the kidney. S-sulfhydration regulates ATP production, anti-oxidative stress, regulation of ER stress and water-sodium balance in the kidney. EGFR: endothelial growth factor receptor; ER: endoplasmic reticulum; Keap-1: Kelch-like ECH-associated protein1; Nrf2: nuclear factor E2-related factor 2; Sirt1: silent mating-type information regulator 2 homolog 1.