Molecular Enzymology and Drug Targets

Keywords

Apoptosis, Caspase, Disease, Diagnosis

Introduction

The programmed cell suicide or apoptosis is a regulatory system for balancing the homeostasis situation during the growth, development and differentiation among multicellular organisms. The appearance of any type of disorders may lead to wide range of diseases including neurological, immunological, and cancerous problems [1-5].

In 1972, Kerr and colleagues described the process of apoptosis (programmed cell suicide/programmed cell death) for the first time [6-8].

Despite a very close relationship between apoptosis and the cysteine protease enzymes family of caspases; they were unknown until the middle of 1990s. Caspases are the essential elements in the process of apoptosis. The performance of a successful apoptosis process is directly associated with inducers, caspase enzymes, related genes and signaling pathways. Thus, the cascade system of caspases has a key role within all steps of the apoptosis process [7,9,10].

Previous studies have revealed that, monomeric procaspases (proenzymes or zymogens) are able to be converted into dimerized active caspases by particular inducers or stimulators. The dimerized caspases are linked together as unite structures via proteins of adapters. The function of caspases is achieved via the cleavage of some related proteins within the cells. Simply, turned on caspases are responsible for turning off the process of cell survival [4,7,11-13].

The role of caspases within the process of apoptosis is very bold. Hence, the main goal of this review is to discuss about different members of caspases.

General characteristics of caspases

The endoproteases of caspases are able to break down peptide bonds via cysteine residues in substrates. Caspases (cysteine dependent aspartate driven proteases) were recognized in some cell lineages of Caenorhabditis elegans which were undergone the process of apoptosis. So, for the first time the importance of caspases regarding to apoptosis feature was recognized in C. elegans [12,14,15].

There are three well-known CED (Cell Death abnormal) proteins such as CED-3, CED-4, and CED-9 which have significant contributions in the process of apoptosis in C. elegans. The basis of apoptosis mechanism in C. elegans is similar to the mammals. There are different functions for CED proteins. The CED-3 as a cysteine protease is the initiator of apoptosis process in C. elegans and CED-4 protein is the stimulator for CED-3 activation while the CED-9 protein is an apoptotic hindrance via inhibiting CED-3 from binding to CED-4. In another word, CED-3 and CED-4 proteins are cell killers whilst CED-9 guarantees the cell survival. The apoptosis pathway in C. elegans is completed by EGL-1 [7,15-17].

The molecular and genetical surveys indicate that caspases, Apaf- 1/NOD like receptors, and Bcl-2 proteins are mammalian versions of CED-3 and EGL-1, CED-4 and CED-9 in C. elegans [7,15].

Caspases involve a wide range of conserved enzymes which catalyze the cell death way irreversibly in mammals including human beings. Caspases encompass an active site with conserved sequence of "QACX(D,Q,R)G" which is recognized as a pentapeptide motif [9,18].

Although the correlation of interleukin-1β-converting enzyme (ICE) or caspase-1 and apoptosis is unclear, it is the first discovered member among caspases family members. There are some common characteristics among caspases. Caspases are 30- 50 kDa zymogens that have similar structures, sequences and specificities. Each caspase is consisted of three parts including an amine (N) terminal, an active site which is located within the large subunit and a small subunit (C terminal), respectively. These three regions are separated from each other via a cleavage site of Aspartic acid. An active caspase, removes the N terminal region and recognized as a tetrameric heterodimer. Thus, an active caspase encompasses two subunits of large and small with an active site within the large one. Several surveys indicate that, negative charged substrates are attracted to the active site; because of positive charge of active site. Moreover, the substrates are linked to the caspase active site throughout their aspartic acid residues. Regarding to amino acid sequences, there are three types of caspases including apoptosis initiators, apoptosis executioners and inflammation mediators (Table 1) [5,9,19].

Many investigations have revealed the diversity of caspases' N terminal prodomains both in sequence and size. These differences are important in caspases functions. Caspases that are known as apoptosis initiators and inflammation mediators possess long prodomains. The long prodomains in procaspases of 8 and 10 involve the death effector domain (DED) while in procaspases of 1, 2, 4, 5, 9, and 12 the caspase recruitment domain (CARD) is replaced [9,19,20].

Mitochondrion and death receptor mediated pathways are two important mechanisms in which procaspases are converted into active caspases [9]. According to the importance of caspases mentioned in Table 1, these enzymes are studied in below:

Apoptosis initiator

Caspases-2, 8, 9, 10

Caspase-2 as an apoptosis initiator is activated via physicochemical inducers such as DNA damages, malnutrition, Heat shock, and cellular spindle disorganization. However, by deletion of apoptotic inducers, the process of caspase activation reduces [7].

Caspase-8 as an important apoptosis initiator is detectable in different parts of the body. FAS receptor as a member of Tumor Necrosis Factor (TNF) receptors is able to activate caspase-8. Several studies show that serine kinases, threonine kinases and Nitric oxide (NO) are inhibitors of caspase-8 activation [7,21].

Caspase-9 is an essential component for activation of apoptosis executioner. An activated caspase-9 is able to activate caspases-3 and 7 which are effective players regarding to appearance of apoptosis demonstrations. So, the triangle of caspase-9, caspase-3 and caspase-7 has a significant role in association with apoptosis demonstrations. It shows that, the inhibition of caspase-9 activity leads to apoptosis prevention [7,22].

Caspase-10 resembling caspase-8 contributes to cytochrome c release from mitochondria and have important role in apoptosis appearance [7,23].

Apoptosis executioner

Caspases-3, 6, 7

All of the effector caspases including caspases 3, 6 and 7 are activated via apoptosis initiators. Caspase-3 has an important role in associated with apoptosis. This caspase achieve its role throughout degradation of nuclear polymerase. Moreover, caspase-3 is responsible for apoptotic features in immune system and has a high similarity with caspases 6, and 7 [7,24].

Procaspase-6 is an independent enzyme which must be activated via caspase-3 or caspase-7; however, some self-activities have been observed during previous investigations. Some kinases are able to inhibit the activity of caspase-6 [7,12,24,25].

Caspase-7 and caspase-3 have several similarities to each other and there is a large overlapping among their activities and substrates. Caspase-7 contributes to apoptosis via influencing on granzyme [7,24].

Inflammation mediators

Caspases-1, 4, 5, 12, 14

A high similarity is recognized among caspases 1, 4, 5 and 12. 1/3 of structural sequences relating to Caspase-1 and CED-3 have overlapping. Caspase-1 contributes in innate immune system via inducing IL-1β. The activity of caspase-1 results in inflammatory apoptosis which is called pyroptosis. Caspase-1 activation is in association with inflammosomes and apoptosomes. UV-light is an important inducer for inflammation mediators. Besides, interferon (IFN) γ triggers the production of caspase-4; while, the secretion of caspase-5 is induced via lipopolysaccharide (LPS). The caspases 4 and 5 are common activators for immature ILs of 1β and 18; thus, these caspases are involved in immunological responses relating to humans [7,9,6-28].

Caspase-12 is in association with apoptotic processes in ER. The caspase-7 is known as caspase-12 activator. As a cascade circulation, the activated caspase-12 activates caspase-9 and the latter triggers caspases 3,6 and 7. Some results indicate a regulatory activity for caspase-12 instead of proteolytic [9,12,29,30].

Caspase-14 is the least evolved member; because of its limited presence among organisms. This caspase is recognized in terrestrial mammals' keratinocytes [12].

Conclusion

Apoptosis is a multifunctional defense system which protects the host's body from infectious, genetical and immunological diseases and disorders. Simultaneously, apoptosis mediates an enzymatic cascade system which plays a vital role in the process of apoptosis. The presence or absence, the rate and concentration of each enzyme reveal the situation of the body and determine the type of diseases. Thus, the study of the type and concentration of the caspase enzymes is valuable criterion for diagnosing and treatment.

In conclusion, the apoptosis and related mechanisms are 3-dimensional process which are used for body protection, disease diagnosis and treatment

Conflict of Interest

There is no conflict of interest for the authors.

Tables at a glance

Table 1

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