What Are Peptides?
The biological significance of proteins was recognized more than two centuries ago. They were considered the primary material required for living organisms. But from the beginning of the 20th century, the significance of protein-like molecules, peptides, became apparent in several life processes.
Figure: The illustration of name and year of peptides discovered in the 20th century.
Source: Creative Peptides
Like proteins, peptides also consist of chains of amino acids and are held together by peptide bonds. Peptides have the same properties as protein molecules. However, unlike proteins, their classes of molecules are small, simpler, and of lower molecular weight. They consist of 2-50 amino acids, unlike proteins which consist of more than 50 amino acids.
Emil Fischer is considered the father of the chemistry of peptides. He coined the term “peptide,” which originated from the word “pepsis,” meaning digestion products of proteins.
This article poses a classification of peptides, their classes, actions, and essential peptide functions in living organisms.
Structure and Classification of Peptides
Peptides are formed by linking two or more amino acids through an amide linkage, called a peptide bond. The formation of peptide bonds occurs by the removal of a hydroxyl group (-OH) from one alpha-amino group and hydrogen (-H) atom from another alpha-amino group, forming a water molecule (H2O). This reaction is called a dehydration reaction.
Peptides are sub-categorized into two groups based on the number of amino acids present in their structures: oligopeptides and polypeptides.
When two or more (but less than 20) amino acids are linked together with the loss of a water molecule, they are called oligopeptides. It also includes dipeptides, tripeptides, tetrapeptides, and pentapeptides. Some examples of naturally occurring oligopeptides are microviridin, cyanopeptolin, microcystins, etc.
Figure: An illustrative structure of dipeptide and tripeptide.
Source: Online Biology notes.
The oligopeptides are synthesized through non-ribosomal pathways, except for cyclamates and microviridin synthesized through ribosomal pathways. There are several ways to identify peptides, and these ways include gel chromatography, HPLC, HPLC-mass spectroscopy, and ion-exchange chromatography.
When 20 or more amino acids are linked together through covalent peptide bonds, they are called polypeptides. One or more polypeptides are involved in the formation of proteins. They have two terminals present in their structure: N-terminal containing an amino group and C-terminal containing a carboxyl group. Some examples of polypeptides include insulin and growth hormones.
Polypeptides are arranged in different structural forms to create different functional proteins. So, according to the number and arrangement of polypeptides, the structure of proteins are categorized into four groups:
- Primary Structure: Only a single polypeptide chain is involved in building this structure with peptide bond formation.
- Secondary Structure: It is formed due to the folding of the polypeptide chain by forming hydrogen bonds between amide hydrogens and carbonyl oxygens of the peptide backbone. Two major secondary structures are alpha-helix and beta-sheet structures.
- Tertiary Structure: It’s a 3-D structure of proteins in which the side chains of amino acids are linked together and folded in several ways. This is via hydrophobic bonds, hydrogen bonds, ionic bonds, disulfide bonds, and Van der Waals interactions.
- Quaternary Structure: It is formed by joining two or more polypeptides together. The chains are held together by hydrogen bonds and Van der Waals forces between nonpolar side chains.
Classes of Peptides and Their Biological Significance
Peptides, based on their functional properties, are categorized into many small groups. Here’s a list of the most commonly studied classes of peptides in organisms, along with their functions and some examples.
1. Antimicrobial Peptides
Antimicrobial peptides, also known as host defense peptides, are a class of peptides that play a role in the innate immune response of all organisms. They are classified into two groups: ribosomally synthesized peptides and non-ribosomally synthesized peptides.
- Non-ribosomally synthesized peptides are elaborated in different organisms (bacteria, fungi, and streptomycetes containing two or more moieties derived from amino acids) and composed of multienzyme complexes. Examples include penicillin, cephalosporin C, vancomycin, and teicoplanin.
- Ribosomally synthesized peptides are produced by nearly all organisms including mammals, amphibians, insects, plants, bacteria, and viruses. They are typically synthesized on ribosomes. Examples include gramicidin S, bacitracin, polymyxin B, human beta-defensin 1, and cattle indolicidin.
2. Bacterial Peptides
As the name suggests, bacterial peptides are fragments of proteins produced by bacteria. They include flagellar peptides, lipoproteins, enterotoxins, and several enzymes.
The peptides secreted from both gram-positive and gram-negative bacteria are both cationic and neutral. These types of peptides are included within bacteriocin that kills specific competitor bacteria, protecting the host bacterium.
Examples include Escherichia coli 7-amino-acid peptide microcin C7 (inhibits protein synthesis), Lactococcus peptide mersacidin (inhibits peptidoglycan biosynthesis), nisin, and epidermin (permeabilizes target cell membrane).
These are small proteins synthesized by neurons to act on receptors and modulate synaptic transmission. The neuropeptides are synthesized by large, inactive precursor proteins, called pre-propeptides.
These proteins are cleaved into several active peptides and produce multiple copies of different neuropeptides. Most neuropeptides act on G protein-coupled receptors (GPCRs) and fall into two families: the rhodopsin-like and the secretin families.
Examples include acetylcholine, epinephrine, norepinephrine, dopamine, serotonin, and Gamma-aminobutyric acid (GABA).
4. Anticancer Peptides
Anticancer peptides (ACPs) are small peptides with a short amino acid sequence that are selective and toxic to cancer cells. The predominant amino acids in anticancer peptides include glycine, lysine, and leucine.
The anticancer peptides are a highly preferred choice among all the other available anticancer therapeutics due to their high selectivity, high penetration, and easy modifications.
The peptides destroy cancer cells via apoptosis and necrosis by lysing or forming pores in the membranes of cancerous cells. These types of peptides, depending on their structure, mode of action, selectivity, and efficacy to specific cancer cells, are divided into three categories:
- Molecularly targeted peptides: They directly act on cancer cells via cytotoxic, anti-proliferative, and apoptotic activities. Examples include Mastoparan I, anticancer peptide SVS-1, and tubulysin analog KEMTUB10.
- ‘Guiding missile’ peptides or binding peptides: They are drug binding peptides that deliver drugs to the targeted cancer cells. Examples are CP-EPS8-NLS (a synthetic peptide derived from nuclear localization signal NLS and epidermal growth factor receptor pathway substrate 8 EPS8) and cell-penetrating peptide TAT-conjugated gambogic acid (GA-TAT).
- Cell-stimulating peptides: They indirectly kill cancer cells by stimulating other cells via immunomodulatory activities and hormone receptors. It includes the E75 peptide breast cancer vaccine (Her2 p369-p377), a melittin-RADA32 hybrid peptide hydrogel-linked doxorubicin, and Tyrosinase-related protein 2 melanoma antigen peptide nanovaccine.
5. Cardiovascular Peptides
- Adrenomedullin peptide: It’s a 52 amino acid peptide playing multiple roles in cardiovascular actions, including reducing blood pressure, anti-inflammation, vasodilation, stimulation of nitric oxide production, and inhibition of myocardial hypertrophy and fibrosis.
- Angiotensin II peptide: It’s the central product of the renin-angiotensin system (RAS). It plays a significant role in causing hypertension, myocyte hypertrophy, myocyte gene reprogramming, fibroblast proliferation, extracellular matrix (ECM) protein accumulation, and other pathophysiology of cardiovascular diseases in humans.
- CGRP: It’s a 37 amino acid neuropeptide belonging to the family of structurally related peptides like adrenomedullin (AM) and amylin (AMY). It binds with GPCRs, known as calcitonin receptor-like receptors (CLR), to activate its functional signaling pathway. It acts as a potent vasodilator and is involved in cardiovascular homeostasis. Any mutation in CGRP may lead to its functional disturbances that can cause diseases like a migraine.
- Natriuretic peptides: In mammals, it’s a peptide family consisting of atrial (A-type) natriuretic peptide (ANP), brain (B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP and BNP peptides are abundantly produced in cardiomyocytes, while CNP is synthesized in endothelial cells and cardiac fibroblasts. They are involved in dilating blood vessels and inducing diuresis/natriuresis by increasing the intracellular cGMP concentration.
- Urocortins: It’s a paralogue (a particular class of homologous gene) of corticotropin-releasing hormone. They regulate pressure and volume in different organs, including the heart, kidneys, adrenals, and vasculature. It’s an ongoing research interest for scientists, and it promises a better understanding of the pathophysiology of ischemia-reperfusion injury, hypertension, and heart failure.
- Urotensin peptides: It’s a peptide hormone consisting of urotensin I (UI) and urotensin II (UII). It was initially discovered in fish urophysis. UI plays several roles in different organisms, including stimulation of cell proliferation and hypertrophy, positive inotropic action, and CNS actions on cardiovascular control. Whereas UII has a vital role in congestive heart failure, hypertension, end-stage renal disease, and diabetes mellitus.
6. Endocrine Peptides
They are short amino acid-chained peptide hormones synthesized and secreted by specialized cells in the endocrine. They are stored in membrane-bound secretory vesicles, which enable their rapid secretion whenever required.
They are water-soluble, and this makes it difficult for them to cross the hydrophobic cell membranes. Thus, they need specific receptors on the cell surface to exert their actions.
Some examples of endocrine peptides include:
- Adiponectin (APN): It’s an anorexigenic peptide involved in multiple functions, including stimulating fatty acid oxidation and glucose uptake in skeletal muscle and adipose tissue. It also improves whole-body insulin sensitivity and increases energy expenditure; however, it suppresses hepatic glucose output by activating AMP-activated protein kinase (AMPK) signaling.
- Leptin: It is majorly produced by adipocytes. It acts as a signaling molecule between peripheral organs and the central nervous system. It has several functions that include regulating numerous endocrine functions relevant for the maintenance of energy expenditure, appetite regulation, body weight control, and the functioning of endocrine organs.
- Atrial natriuretic peptide (ANP): It was initially purified from the rat’s heart and was the first natriuretic peptide (NP). It is involved in several activities, including antiproliferation, anti-fibrosis, anti-inflammation, insulin-like functions, cardiovascular homeostasis, and regulation of bone growth.
- Orexins: It has two subtypes: Orexins A and B. These are involved in regulating feeding, wakefulness, sleep, and energy homeostasis. They are synthesized in multiple organs, including the intestines, pancreas, adrenal gland, reproductive tract, and adipose tissue.
- Pituitary adenylate cyclase-activating polypeptide (PACAP): It belongs to the superfamily of the vasoactive intestinal polypeptide (VIP)-glucagon peptides. PACAP exerts neuroendocrine, paracrine, and autocrine control of the pituitary gland activity, thyroid glands, testis, ovary, adrenal medulla, adrenal cortex, and endocrine pancreas.
7. Antifungal Peptides
- Peptaibols: It consists of four categories of peptides having both antifungal and antibacterial properties. There are nine membrane-active peptaibols, two nonadecapeptide peptaibols, four nonadecapeptide peptaibols with antibacterial and antifungal activities, and two linear 19-amino-acids.
- Cyclic antifungal peptides: These are antifungal peptides having cyclic structures. Their examples include Isarfelin (having inhibitory activity against the fungi, Rhizoctonia solani, and Sclerotinia sclerotiorum), eujavanicin A (suppresses growth in the human pathogenic filamentous fungus Aspergillus fumigatus), and echinocandin type l antifungal lipopeptide (used in the therapy of deep-seated mycoses).
- Fungal peptides with ribosome-inactivating activity: Fungi, like molds and mushrooms, synthesize variant peptides with ribonuclease- and ribosome-inactivating activities. They include RNases and ubiquitin-like peptides from different fungi.
8. Opiate Peptides
The endogenous and exogenous opioids exert several physiological and pharmacological effects through receptors of four different subtypes. It include μ (μ1, μ2), 𝜹 (𝜹1, 𝜹2), 𝜿 (𝜿1, 𝜿2), and ε (ε1, ε2).
They regulate other endocrine systems like the hypothalamic-pituitary-adrenocortical axis and the phenomenon of stress-induced analgesia.
Endogenous opiate peptides are better studied than exogenous peptides. They consist of three families of peptides based on their origin:
- The proopiomelanocortin (POMC) family of peptides
- The proenkephalin A (PA) family of peptides
- The prodynorphin (PD) family of peptides
Some peptides like cholecystokinin (CCK), neuropeptide FF (NPFF), and melanocyte inhibiting factor (MIF)-related peptides possess anti-opioid properties. But these peptide families also include some peptides harboring opioid-like properties, and that’s why they are also known as “opioid modulating” peptides.
9. Plant Peptides
Plant peptides are peptides that originated in plants and they possess significant health benefits in humans. They lower blood pressure and cholesterol levels and inhibit enzymes within the renin-angiotensin-aldosterone system (RAAS).
Other benefits include their anti-inflammatory activity, anticancer and immunomodulatory activities, prevention of and protection against oxidative damage through free radical scavenging activities, and antimicrobial activity.
Plant peptides are categorized into three groups based on their functional response:
- Plant-derived peptides for cardiovascular health: Examples include ACE-I- and renin-inhibiting bioactive peptides generated from plants, including potato, yams, rapeseeds, lentils, red seaweed, and many kinds of cereal.
- Plant-derived antioxidant peptides: Examples include glutathione peptide, β -conglycinin, and trypsin hydrolysate. Most of the antioxidants are rich in amino acids like histidine (His), tryptophan (Trp), tyrosine (Tyr), and lysine (Lys).
- Anticancer and antimicrobial plant-derived peptides: Antimicrobial peptides derived from plants are a novel alternative for cancer treatment. It includes peptides like thionins, plant defensins, cyclotides, and small cationic peptides.
- Plant-derived peptides in controlling type II diabetes: These peptides work against diabetes by inhibiting the enzyme dipeptidyl peptidase-IV. It includes peptides that are inhibitors of dipeptidyl peptidase-IV and are commonly extracted from plants like Opuntia streptacantha, Trigonella foenum-graecum, Momordica charantia, Ficus benghalensis, Polygala senega, and Gymnema sylvestre.
10. Venom Peptides
Toxins developed in animals are strategies to protect themselves from different predators and/or capture their prey.
Several of these venoms studied are found in animals with envenomation apparatus like cone snails, spiders, scorpions, snakes, the Gila monster lizard, and sea anemone.
Venom peptides act as natural ligands of ions channels and different receptors they bind to initiate physiological responses. Based on these characteristics, they are categorized into eight groups:
- Calcium channel peptides
- Sodium-channel toxins
- Potassium-channel toxins
- Chloride-channel toxins
- Toxins inhibiting nicotinic acetylcholine receptors
- Noradrenaline transporter inhibitors
- NMDA receptor antagonists
- Neurotensin receptor agonists
The application of these peptides in healthcare sectors demands many issues associated with their safety, pharmacokinetics, and delivery to be addressed.
Peptides are a class of biological molecules that have essential roles in fundamental physiological processes and are required for many biochemical processes. They are small molecules made by sequential arrangements of 2-50 amino acids. The difference between peptide and protein is that proteins are large chains of amino acid sequence (50 or more) with different specialized structures.
The benefits of peptides have established a special place in the pharmaceutical landscape. And the innovations in peptide therapeutics are believed to rise in the future by expanding into new indications and molecular targets, exploiting novel chemistry strategies to broaden molecular diversity, and engineering enhanced pharmaceutical properties.
Further, the study of peptide benefits and chemistry opens a door for scientists to unravel its hidden potentials. It can be identifying novel targets and receptors of peptides, the discovery of more peptides in organisms and their functional properties, or the discovery of sustainable peptide-based drugs.
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