Effects of environmental electrophiles on the body and response mechanisms
Because environmental electrophiles have an
electron-deficient (electrophilic) part in the molecule, it easily binds
covalently to an electron-rich (nucleophilic) thiol group of a protein
to form an adduct (electrophilic modification). This electrophilic modification
induces structural changes in the protein. Consequently, cellular functions
of the protein and coupled intracellular signaling pathways are altered,
and the whole body is affected (Figure 1).
Our bodies have biological response systems that have adapted to this
electrophilic modification. Environmental electrophiles that have entered
the body first react with highly reactive sensor proteins (protein tyrosine
phosphatase 1B and Kelch-Like ECH-Associated Protein 1). Structural changes
caused by the electrophilic modifications activate response molecules (epidermal
growth factor receptor and nuclear factor-erythroid-derived 2 -related
factor 2), which, by then, have been down-regulated by sensor proteins.
Activated response molecules trigger various signaling pathways involved
in survival and proliferation of cells as well as providing protection
from toxicity. Therefore, homeostasis of the body can be maintained. However,
if the body is exposed to excessive environmental electrophiles, these
electrophiles nonspecifically react with proteins causing disruption in
intracellular signaling and disturbance of homeostasis. This process eventually
leads to disease (Figure 2).
We are currently working on identification of novel sensor proteins that respond to environmental electrophiles, and are investigating molecule-dependent signaling response regulated by these sensor proteins. We are also trying to prove the bilateral mechanism derived from activation of various signaling pathways that are triggered by electrophilic modification of sensor proteins is involved in maintenance of homeostasis and disruption of these signaling pathways due to increased exposure to environmental electrophiles.
Early defense systems of the body mediated by reactive sulfur species
As described above, our bodies have sensor protein-dependent response
systems that are activated in response to environmental electrophiles.
This biological response, however, has a threshold level up to which environmental
electrophiles elicit no response. This implies the presence of early defense
systems that capture and deactivate environmental electrophiles that have
entered the body, before they react with sensor proteins. Recently, we
have discovered, through collaborative research with Professor Akaike from
Tohoku University, that cystathionine-γ-lyase is the primary enzyme responsible
for in vivo production of reactive sulfur species which are highly nucleophilic
and antioxidative. Reactive sulfur species are cysteine persulfide- and
glutathione persulfide-related compounds containing an extra sulfur atom
attached to the thiol group of cysteine, glutathione, and some other sulfur-containing
compounds. Their chemical properties are characterized by the presence
of a mobile sulfur atom in the molecule (Figure 3a).
This suggests the presence of early defense systems, in which the mobile
sulfur of reactive sulfur species reacts in a compensatory manner with
environmental electrophiles in the body to neutralize their electrophilicity
and prevent electrophiles from affecting the body (electrophilic protein
modification) (Figure 3b).
Using cystathionine-γ-lyase gene-deficient mice, we are currently trying to elucidate the reactive sulfur species-mediated early defense systems against environmental electrophiles in the body. Furthermore, we have discovered that reactive sulfur species are also present in plants, and we are conducting research/analyses aiming to develop plant-derived reactive sulfur species supplements for mitigation of environmental risks.