Enzymes for Disease Treatment: A Review Volume 49- Issue 3
Girum Tefera Belachew*
Department of Biotechnology, College of Natural and Computational Sciences, Debre Birhan University, Ethiopia
Received: March 15, 2023; Published: March 29, 2023
*Corresponding author: Girum Tefera Belachew, Department of Biotechnology, College of Natural and Computational Sciences,
Debre Birhan University, P.O. Box 445, Debre Birhan, Ethiopia
Background
Since ancient times, enzymes have been widely used in a variety of sectors. Unfortunately, until the late
1950s, when scientists finally discovered the gold mine, they were sitting on, their potential as medicines
lay dormant. The use of enzyme therapy for the treatment of numerous diseases, such as lysosomal storage
disorders, cancer, Alzheimer’s disease, irritable bowel syndrome, exocrine pancreatic insufficiency, and
hyperuricemia, has increased significantly during the past few decades. Gene therapy, the treatment of
microbial infections, and wound healing are further uses for enzymes.
Keywords: Disease; Human study; Therapeutic; Treatment
Since 6000 BC, enzymes have been unwittingly used in a wide
range of industries. Even after Payen and Persoz described the first
enzyme in 1833, enzymes were only employed commercially, and the
majority of their potential remained untapped [1,2]. Yet, a clear image
of the use of enzymes for therapeutic treatments slowly emerged
with the development of better lab equipment and the separation
of enzymes in pure form. We describe enzyme therapy as the use of
biological globular proteins that catalyze key biochemical reactions
in their natural state or when fused with particular chemicals that
enhance their properties in order to cure diverse problems. According
to PubMed metrics, enzyme therapy has developed into a fastexpanding
subject in recent years, with more than 300 publications
relating to «enzyme replacement therapy» alone published every
year over the past ten years, as seen in (Figure 1).
The earliest widely known application of enzymes for medicinal
purposes was in enzyme replacement therapy. Dr. Christian de Duve
suggested in 1964 that enzymes might be used to treat lysosomal
storage disorders [3]. Since its inception, enzyme replacement
therapy has advanced significantly and is now used to treat a variety of
enzyme deficiency disorders, including adenosine deaminase-severe
combined immune deficiency [4], Gaucher disease [5], adenosine
deaminase-fabry disease [6], Fabry disease [7], Pompe disease [8],
Hunter syndrome, Hurler-Scheie syndrome [9], Sly syndrome [10],
Morquio A syndrome [11], Tay-Sachs disease [12], Wolman disease
[13], adenosine deaminasesevere combined immune deficiency
[4], hypophosphatasia [14], metachromatic leukodystrophy [15],
Sphingomyelinase deficiency [16], homocystinuria [17], Maroteaux-
Lamy syndrome [18], alpha-mannosidosis [19], and ceroid
lipofuscinosis type 2 [20].
The treatment of exocrine pancreatic insufficiency, which can
occur in a number of disorders including cystic fibrosis, chronic
pancreatitis, and celiac disease, with enzymes is known as pancreatic
enzyme replacement therapy [21]. In addition, the therapeutic
application of enzymes has expanded in the modern period to include
gene therapy [22], the treatment of cancer [23], the healing of wounds
[24], the enhancement of irritable bowel syndrome patients’ lives [25],
and the prevention of antibiotic-resistant microbial infections [26]. In
this post, we go through the characteristics of several enzymes and
how well they work to treat certain diseases. Based on the numerous
disorders that they are used to cure; the enzymes have been divided
into divisions. An update on recent advancements in enzyme research
and their use as medicines is also provided in this article.
Figure 1.
Medicinal Value of Enzymes
Anti-Alzheimer’s Disease: Alzheimer’s disease is a serious illness
that can cause someone to vanish long before they really pass away.
The development of -amyloid peptide plaques and neurofibrillary
tangles in the brain, which results in the deterioration of the nervous
system, is the pathological condition linked with Alzheimer’s disease.
This buildup of amyloid plaques and neurofibrillary tangles causes
extensive oxidative damage to neurons, which ultimately results in
cell death. Dementia progresses and the cognitive system becomes
severely dysfunctional as a result of neuronal loss. The proteolytic
activity required to break down amyloid peptides in the brain
into swiftly removed, nonneurotoxic chemicals has been found in
numerous enzymes in recent years.
The term «amyloiddegrading enzymes» refers to these enzymes.
Serine proteases, aspartyl proteases, cysteine proteases, and zinc
metalloprotease enzymes are the several types of enzymes that have
been utilized to treat Alzheimer’s disease [22]. The Neprilysin family
of enzymes is one of the zinc metallopeptidase enzyme families.
Neprilysin enzymes have been seen to break down hydrophobic
-amyloid plaques’ N-terminal end into little peptides with fewer than
fifty amino acid residues. The breakdown of these betaamyloid plaques
was shown to be significantly reduced in mice whose expression of
the enzyme Neprilysin was knocked off. Neprilysin, Neprilysin-2,
Endothelin-Converting Enzyme-1, and Endothelin-Converting
Enzyme-2 are enzymes from the Neprilysin family that have been
linked to the elimination of -amyloid plaques in the brain. The insulin
degrading family of zinc metallopeptidases, which differs from the
Neprilysin family in terms of structure and catalytic function, has
been discovered to be connected to the clearance of amyloid plaques
from the brain. One of the enzymes in this family that has been proven
to dissolve beta amyloid plaques is inulysin. Furthermore, it has been
discovered that even these insulin degrading enzymes’ inactive form
aids in the breakdown of -amyloid plaques by acting as a chaperone.
It has been noted that the angiotensin-converting enzyme cleaves the
more harmful -amyloid-42 to the less harmful -amyloid-40.
Moreover, it has been observed to cleave -amyloid-40 in particular
locations. The mono-carboxypeptidase enzyme angiotensinconverting
enzyme has been seen to cleave-amyloid-43 to produce
amyloid-42. Matrix metalloproteinase-2 and matrix metalloprotease 9 have been seen to cleave neurofibrillary tangles [27] serine protease
known as plajin can break down amyloid fibrils and plaques. Little
amounts of an oligopeptidase enzyme termed acyl-peptide hydrolase
are created by cells via a poorly understood mechanism. After the
13th, 14th, or 15th amino acid, this enzyme has been seen to break
both oligomeric and monomeric -amyloid plaques. In mouse models,
the cysteine protease enzyme cathepsin B has been shown to lower
the concentrations of -amyloid in the brain. It has been noted that
the zinc ectopeptidase enzyme glutamate carboxypeptidase breaks
down amyloid plaques in the brain into amyloid-14, amyloid-18, and
amyloid-35 [28].
Anti-Cancer Activity An extremely fatal terminal condition
known as pancreatic carcinoma causes aberrant cell division in
pancreatic cells, which results in the growth of metastatic tumors.
Precancerous lesions that develop into pancreatic carcinoma can
be roughly categorized as pancreatic intraepithelial neoplasia,
intraductal papillary mucinous neoplasms, and mucinous cystic
neoplasms. The type of pancreatic intraepithelial neoplastic lesions
most frequently seen to develop into metastatic tumors are these.
Due to their size and rapid growth into carcinomas and metastases
to other tissues, these lesions are also difficult to identify and do not
give enough time for therapy. A propensity for pancreaticancer has
been linked to mutations in a number of genes, including KRAS, TP53,
SMAD4, ATM, BRCA1, BRCA2, PALB2, PRSS1, p16/CDKN2A, MLH1,
and STK11 [29].
Hepatocellular carcinoma is a highly typical metastatic malignant
tumor that can result in tissue necrosis and organ failure in the liver
by causing a number of clinical alterations. Hepatitis C infection,
excessive alcohol consumption, and aflatoxin B1 exposure are a few
of the most prevalent risk factors [30]. Melanomas are cutaneous
malignant metastatic tumors with a high mortality rate that have been
on the rise recently. These cancers are brought on by a confluence of
hereditary and environmental factors. Exposure to ultraviolet light is
one of the main causes of melanoma. Lesions on the skin that show
uneven borders and changes in pigmentation and hue are indicative
of melanoma. In a 1999 study, it was discovered that including
proteolytic enzymes in the diet helped patients with pancreatic
cancer live longer.
The study’s small sample size, however, makes it difficult to
draw many conclusions [31]. Hepacid is a polyethylene glycosylated
arginine deiminase enzyme that is injected intramuscularly and is
being researched as a therapy for hepatocellular cancer. Another
polyethylene glycosylated arginine deiminase-derived enzyme used
to treat metastatic melanoma is called melanocid. Both of these
enzymes break down and limit the amount of arginine, an essential
amino acid required for the growth of cancerous cells [32]. Although
arginine deiminase enzymes have been shown to have a considerable
impact on mice, their usage in humans is still restricted due to their
brief serum half-life. Furthermore, due to their microbial origin, these
enzymes have been found to have a significant immunogenicity in
mammals.
Despite the fact that the enzymes were seen to have a considerable
impact on certain patients during clinical trials, the outcomes were
incredibly uneven, and they were also seen to have a number of
undesirable side effects, including higher ammonia levels. These
genes, which produce the arginine deiminase enzyme, have been
identified from a variety of bacteria, including Streptococcus sangria,
Mycoplasma arginini, and Pseudomonas aeruginosa, and are primarily
overexpressed in Escherichia coli BL21 cells [33]. The disorder known
as acute lymphoblastic leukemia is brought on by the malignant
transformation and proliferation of lymphoid progenitor cells. Many
physical symptoms, including anemia, thrombocytopenia, weight
loss, leukopenia, fever, bruising propensity, hepatosplenomegaly, and
night sweats, are used to describe this illness [34].
This kind of leukemia can now be treated using the enzyme
L-asparaginase. This enzyme breaks down L-asparagine into
ammonia and L-aspartate, which causes cell death. Unfortunately,
using this enzyme for treatment has a number of disadvantages,
including toxicity and cell resistance to the enzyme. Erwinase and
Oncaspar are the two enzymes that have been approved for use in
the management of acute lymphoblastic leukemia. L-asparaginase is
an enzyme, and oncaspar is a polyethylene glycosylated version of it.
The enzyme is polyethylene glycosylated, which improves stability
and plasma retention duration while lowering immunogenicity and
proteolysis [35]. Acute lymphoblastic leukemia is being treated with
Erwinase, a different L-asparaginase enzyme made from Erwinia
chrysanthemi [36].
Antidiabetic Effect: In glucose hemostasis, the enzyme
glucokinase is crucial. A protein called glucokinase regulatory protein
controls its function [37]. Transcriptional factors control glucokinase
activity in the pancreas, whereas glucokinase regulatory protein
controls it in the liver. The first stage in the metabolism of glucose is
catalyzed by the enzyme glucokinase, and mutations in this enzyme
are linked to young-onset diabetes with maturity. High levels of this
enzyme and enhanced glucose tolerance were caused by a high-carb
diet [38].
Anti Cardiovascular Diseases: In the world, cardiovascular
disease (CVD) is the leading cause of death. This severe disease is
thought to be treatable by ERT. First, urokinase is an enzyme whose
substrate is plasminogen, an inactive form of the serine protease
plasmin. This enzyme turns plasminogen into plasmin, which sets
off a proteolytic cascade that takes part in the extracellular matrix’s
breakdown during thrombolysis (ECM). Many vascular disorders can
be treated with the use of this procedure [39]. Second, the enzyme
nattokinase promotes fibrinolytic activity by inactivating plasminogen
activator inhibitor 1 [40].
Troubleshooting Enzyme Treatments: For a variety of diseases,
enzymes have been employed as therapeutic medicines [41-43].
Studies on the potential of enzymes as therapeutic agents and on the
metabolic pathways involved in many diseases have benefited from
advancements in both biotechnology and protein engineering [44].
Recombinant enzymes have consequently become new therapeutic
options for a variety of disorders, including cancer and genetic
anomalies (LSD, CF, etc.) [44,45]. Enzyme treatments must overcome
enzyme fast clearance in vivo, undesired off-target interactions, and
patient immune response to become commonly used medications.
The most amazing therapeutic enhancement strategies to date
include the encapsulation, molecular alteration, and active monitoring
of immune response. Applying the enzyme medication directly to the
intended tissue is one of the simplest strategies to avoid undesirable
off-target reactions. Deoxyribonuclease has been administered via
eye drops for individuals with dry eye illness [46] in this context, and
urokinase has been delivered via catheter to dissolve intraluminal
clots [47]. Other strategies, such as enzyme encapsulation and
modification as well as monitoring of patients’ immune reactions, are
being developed, though, to overcome the specific limitations [48-60].
Many disorders are treated with enzyme therapy. There are
various stages of clinical trials for some enzymes. Pharmaceutical
companies are now producing safer, less expensive enzymes with
increased potency and specificity thanks to advancements in
biotechnology [61-78]. Enzymes and medications have the potential
to work synergistically to treat a variety of ailments and lessen the
adverse effects of specific medications [79-84]. Such biochemical
leads can be developed for therapeutic evaluation thanks to the high
degree of specificity of enzymes and the fast-growing competence in
macromolecular chemistry (Table 1).
Table 1. Enzyme therapy research as per published literature.
Jameson E, Jones S, Wraith JE (2013) Enzyme replacement therapy with laronidase (Aldurazyme((R))) for treating mucopolysaccharidosis type I. Cochrane database Syst Rev 4: CD009354.