Article Type : Review Article
Authors : Divocha V
Keywords : Infectious process; Proteinases; Regulation
Understanding the regulatory function of proteolytic enzymes
is of fundamental importance in the biological control of physiological
processes. Dysfunction of proteinases and their regulation leads to viral,
oncological, cardiovascular and other diseases. Proteolytic activation is most
common among viruses of different taxonomic groups and concerns mainly
glycoproteins, which perform the functions of adsorption and fusion.
Over the past 10 years,
the concept of the role of proteolytic enzymes in the body has changed
significantly. It became apparent that proteolysis is a special form of
biological control [1,2]. Analysis of extensive material has shown that limited
proteolysis serves as a triggering mechanism for many biological processes and
provides a rapid physiological response of the body to changing conditions or
an external signal [3-6]. Understanding the regulatory function of proteolytic
enzymes is of fundamental importance. This is important both for deciphering
the most complex biological processes, such as cell division and
transformation, morphogenesis, metamorphosis, metabolic adaptive restructuring,
etc., and for elucidating the molecular basis of pathology [7-8]. It is already
clear that the dysfunction of proteolytic enzymes and their regulation
underlies many pathological conditions [9]. These include disorders of the
cardiovascular system, acute ichronic inflammatory processes, oncological and
endocrine diseases, nervous and muscular dystrophies, viral diseases,
psychological and nervous disorders [10-13]. It is obvious that clarification
of the specific functions of individual proteinases is a necessary condition
for understanding the pathogenesis of these diseases, their diagnosis and
rational therapy.
However, the regulatory
role of proteolytic enzymes is diverse and not yet fully understood. The
participation of proteolytic enzymes in regulation is associated with two types
of proteolysis: complete degradation of protein molecules and limited
proteolysis reactions, i.e. specific hydrolysis of certain peptide bonds. By
causing complete degradation of protein molecules, proteinases determine the
rate of protein breakdown in the body and are involved in regulation [14,15].
Proteinases are involved in the fate of protein and its transformation at the
earliest stages of biosynthesis and accompany the protein. Proteinases are
involved in protein processing by removing the initiator amino acid or signal
peptide from the synthesized precursor protein, which determines the start of
translation and transport of the polypeptide chain. This often occurs during
the growth of the half-peptide chain or immediately after its completion. They
activate inactive precursors, a kind of reserve form of physiologically active
peptide proteins. In many cases, this is the beginning of many physiological
processes [16]. Proteinases cause modification and inactivation of active
proteins. This (especially in the case of key metabolic enzymes) can lead to a
restructuring of metabolism, to "switching on" or p2 for virology
(continued): "switching" of physiological processes, as well as the
implementation of the degradation of protein molecules. Restricted proteolysis
is the easiest way to obtain a diverse set of products with different
physiological properties. Therefore, with the help of specific proteinases, the
information encoded in the same biosynthetic precursor can be used to the
fullest extent. Indeed, with the formation of several active products from one
precursor, a rapid generalized response of the organism to an external signal
can be achieved. This is the case, for example, with painful stress. In
response to a nerve impulse, ACTH-releasing factor enters the pituitary gland
from the pain receptor from the hypothalamus. It causes rapid release from POMK
ACTH, Beta-LPG and Beta-endophin. Each of them acts on its own target tissues,
causing cascades of biochemical reactions that determine the complex response
of the body to pain [17].
To understand the role
of proteinases in the bio control of physiological processes, it is necessary
to know the mechanisms of regulation of their activity. They are carried out
mainly in 3 ways:
·
Many
proteolytic enzymes are synthesized as inactive precursors. For the formation
of enzymes, activation of zymogens is required [18,19].
·
A
powerful system of proteinase inhibitors is present in blood plasma, cells and
tissues, specifically blocking the activity of individual enzymes or groups of
enzymes. Proteinase activity can appear only after inactivation or removal of
the corresponding inhibitor. Imbalance in the proteinase-inhibitor system is
often the cause of the pathological process [18].
·
In
many cases, proteinases and their substrates are spatially separated. They can
be localized both in different subcellular fractions of the same cell, and in
different types of cells and tissues; in some cases, they can be found in
different parts of the body [17].
Coordinated Functioning
of all mechanisms of regulation of proteinase activity, namely: spatial
association of proteolytic enzyme and substrate due to transport of any
component, formation of enzymes from an inactive precursor and removal of an
inhibitor makes it possible to carry out strict temporal and spatial control of
physiological processes and their rapid implementation Proteolytic activation
is widespread among viruses of various taxonomic groups. In picorn and
toraviruses, cleavage of the precursor protein is the main mechanism leading to
the formation of functional proteins. Most other viruses have proteolytic
activation and mainly concerns viral glycoproteins that perform adsorption and
fusion functions. As a result of limited proteolysis, the protein molecule is
cleaved into two subunits, such as the hem agglutinin of the influenza virus,
or a small fragment is cleaved from it, such as in both glycoproteins of
paramyxoviruses, HN and F [20].
Proteolytic activation is a highly specific
process carried out by certain proteinases of cellular or viral origin [21].
Thus, the proteolytic activation of influenza viruses and paramyxoviruses is
carried out by trypsin-like proteinases of the cell, which hydrolyze the
peptide bond between arginine and lysine, chymotrypsin and hemolysis cleave the
precursor protein with a shift by 3 and 1 amino acid, respectively, and at the
same time proteolytic activation does not occur, and the vision fusion the cell
does not occur [22]. The fusion proteins of influenza viruses and
paramyxoviruses are activated by many proteinases. Both these and other
proteinases are found in the chorionallantoic fluid of a chick embryo, but upon
fractionation it can be separated [23]. For maximum cleavage of influenza virus
hem agglutinin and Sendai virus F-protein in vitro, it took about 4 hours of
incubation at t-37 C. Proteolytic activation is an important event in the
infectious cycle of viruses. If it is violated, the assembly of viral particles
will occur, however, the forming virions will not be infectious, since they do
not contain active fusion proteins that ensure the penetration of the virus
into healthy cells. Therefore, proteolytic activation determines the infectious
activity of the virus and its ability to generalize infection. Apparently, the
properties of the virus to infect certain tissues of the body are determined by
the presence in organs and tissues of enzymes necessary for the proteolytic
activation of viral progeny. The importance of proteolytic activation in the
infectious process, its versatility for proteolysis inhibitors is a
prerequisite for its use as a target for the treatment of viral infection. This
approach to the therapy of viral diseases opens up prospects for the creation
of drugs with a wide antiviral spectrum of action, since for certain viruses it
is possible to select specific inhibitors of proteolysis that effectively block
proteolytic processing. Now proteolytic enzymes are of interest in almost all
areas of medicine. This is due to the fact that a number of diseases are
currently known, in the pathogenesis of which proteinases are involved. If we
analyze what kind of malfunctions and regulation of proteinases lead to
pathology, the following reasons can be distinguished:
·
Disruption
of proteinase formation or the appearance of a defective enzyme, which occurs,
for example, in some hereditary diseases, in particular hemophilia [24].
·
The
appearance of a foreign proteinase, this is observed in viral and some
bacterial infections [25].
·
Violation
of regulation of proteolytic activity, in particular, imbalance in the
proteinase-inhibitor balance [26,27]. This may be due to a defect in the
inhibitor and is observed for example, with emphysema of the lungs and some
forms of muscular dystrophy.
·
In
many cases, pathological processes are associated with the release of
intracellular enzymes. This occurs in acute and chronic inflammations of
various origins [28]. The processes of tumor invasion and metastasis are also
associated with the release of proteinases. There is evidence of a correlation
between the metastatic potential of some tumors and the activity of certain
proteinases [29]. In many cases, the functions of certain proteinases have not
yet been established, and the elucidation of their specific role in the
development of a particular pathology should contribute not only to
understanding the molecular basis of various diseases, but also to outline the
ways of their scientifically grounded diagnosis and rational therapy.