Short answer: Yes, many peptides occur in nature, and many are also made in the lab. Chemically, a peptide is an amide built from two or more amino acids [1]. That definition says nothing about origin. In living cells, peptides come from at least three routes: ribosomes, nonribosomal peptide synthetases (NRPSs), and small dedicated enzyme pathways such as the one that makes glutathione [4][6][7][10]. In the lab, most peptides are made by solid-phase peptide synthesis (SPPS) [13][15].
This article is educational chemistry for research readers. It does not cover dosing, health effects, or use in people or animals.
What counts as a peptide
ChEBI defines a peptide as an amide derived from two or more amino carboxylic acid molecules, formed by a covalent bond from the carbonyl carbon of one to the nitrogen atom of another, with formal loss of water [1]. The National Human Genome Research Institute describes a peptide as a short chain of amino acids, typically 2 to 50, linked by peptide bonds. It calls a chain of 51 or more a polypeptide [2]. OpenStax Organic Chemistry describes peptides and proteins as amino acid polymers whose residues are linked by amide (peptide) bonds [3].
These definitions are structural. They describe building blocks and bonds, not where a sample came from [1][3]. That is why "natural" and "synthetic" describe how a peptide was made, not a different kind of molecule. For the basics, see What Are Peptides? and What Is a Peptide Bond?.
Route 1: Ribosomal peptides
The best-known natural route is translation. OpenStax Biology 2e describes translation as decoding an mRNA message into a polypeptide. A peptide bond forms when the amino group of one amino acid bonds with the carboxyl group of another. Ribosomes catalyze this reaction, and each bond releases one water molecule [4]. The same dehydration chemistry links every residue in a chain, and the finished chain has a free amino (N-terminal) end and a free carboxyl (C-terminal) end [5].
Ribosomes don't only make large proteins. A 2013 Natural Product Reports review by Arnison and co-authors describes ribosomally synthesized and post-translationally modified peptides (RiPPs). It calls them a rapidly growing class of natural products made in all three domains of life [6]. Nearly all RiPPs start as a longer precursor peptide, typically about 20 to 110 residues, encoded by a structural gene. The part that becomes the final product is called the core peptide. In most RiPPs, a leader peptide sits on the N-terminal side of the core peptide and is usually important for recognition by the modification enzymes [6]. The review's RiPP definition also sets a 10 kDa size limit [6].
Oxytocin is a familiar natural peptide. PubChem's ChEBI-sourced description calls it a cyclic nonapeptide with the sequence CYIQNCPLG. It classes oxytocin as a peptide hormone of the posterior pituitary and a heterodetic cyclic peptide [12].
Route 2: Nonribosomal peptides
Some natural peptides are never made on a ribosome. Nonribosomal peptide synthetases (NRPSs) are large multienzyme machines that build peptides with wide structural diversity [8]. Hur, Vickery, and Burkart describe nonribosomal peptides as natural products from bacteria and fungi. Each NRPS module adds one monomer unit to the growing product, and each module is made of separate catalytic domains [7].
NRPS products are not limited to the standard building blocks. According to the same review, they can contain the 20 canonical L-amino acids plus non-proteinogenic amino acids, heterocyclic rings, sugars, and fatty acids [7]. Süssmuth and Mainz list penicillin, vancomycin, bleomycin, and cyclosporine among NRPS-assembled compounds [8].
D-amino acids show up in natural peptides
A common assumption is that natural peptides contain only L-amino acids. That is not always true. Ogasawara and Dairi note that D-amino acid residues have been found in peptides from many eukaryotes and prokaryotes [9]. One example is the bacterial peptidoglycan building block UDP-MurNAc-L-Ala-D-Glu-meso-diaminopimelate-D-Ala-D-Ala [9].
The review describes three machineries that put D-residues into peptides [9]:
- NRPS epimerization domains. In gramicidin S synthetase, the first module has an adenylation (A) domain that recognizes L-Phe, a carrier (PCP) domain that holds it, and an epimerization (E) domain that epimerizes it.
- Lantibiotic enzymes. In these ribosome-derived peptides, a D-Ala unit inside lanthionine forms when L-Ser is turned into dehydroalanine and a cysteine thiol then attacks it.
- Radical-SAM enzymes. In polytheonamide, a 48-residue ribosome-derived peptide, one enzyme (PoyD) epimerizes many different residues in the precursor peptide.
Route 3: Small peptides made by dedicated enzymes
Glutathione shows a third natural route. PubChem describes it as a tripeptide: glutamic acid attached through its side chain to the N-terminus of cysteinylglycine [11]. Its formula is C₁₀H₁₇N₃O₆S, with a molecular weight of 307.33 [11].
Lu's 2013 review explains that glutathione synthesis from its amino acids takes two ATP-requiring enzyme steps. First, glutamate-cysteine ligase (GCL) joins glutamate and cysteine to form γ-glutamylcysteine. Then glutathione synthetase (GS) adds glycine [10]. The glutamate-cysteine link uses glutamate's γ-carboxyl group instead of the usual α-carboxyl group [10]. More on this molecule: Glutathione Research Peptide (GSH).
Route 4: Synthetic peptides made in the lab
Laboratory synthesis is the other main source. OpenStax Organic Chemistry explains that R. Bruce Merrifield introduced the solid-phase method. In it, the growing chain is covalently bonded to small polymer resin beads instead of being free in solution. The original procedure used polystyrene resin. A common procedure uses Wang resin with the Fmoc protecting group [13]. The Nobel Prize in Chemistry 1984 went to Merrifield "for his development of methodology for chemical synthesis on a solid matrix" [14].
A 2014 review of peptide impurities states that most peptides today are made by SPPS [15]. Our peptide synthesis guide walks through the SPPS cycle and the Fmoc and Boc chemistries.
Natural vs synthetic: what actually differs
If two samples have the same sequence, stereochemistry, and modifications, they are the same compound under a structural definition [1]. What can differ is everything else in the sample. D'Hondt and co-authors group common synthetic peptide impurities as follows [15]:
- Deletion and insertion sequences, linked to inefficient Fmoc deprotection and excess amino acid reagents
- Racemization during Fmoc deprotection, which gives diastereomeric impurities
- Peptide-protection adducts from incomplete side-chain deprotection, plus side reactions with synthesis reagents
- Oxidation products and dimers or oligomers
- Counter-ions such as trifluoroacetate, left over from SPPS or purification
- Degradation products from β-elimination, diketopiperazine, pyroglutamate, and succinimide formation
FAQ
Are peptides natural or synthetic? Both. Living cells make peptides on ribosomes [4][6], on nonribosomal peptide synthetases [7][8], and through dedicated enzyme pathways like glutathione synthesis [10]. Labs make most peptides by solid-phase synthesis [13][15].
Is a synthetic peptide different from a natural one? Not if the structure is the same. Peptide definitions are structural [1]. The practical differences are in the impurity profile, which depends on how the material was made and purified [15].
Do natural peptides contain only L-amino acids? No. D-amino acid residues have been found in peptides from eukaryotes and prokaryotes, including NRPS products and some ribosome-derived peptides [6][9].
Are all natural peptides made by ribosomes? No. Nonribosomal peptides are built by multimodular NRPS enzymes [7][8]. Glutathione is made by two ATP-requiring enzyme steps [10].
Are peptides the same as steroids? No. They are different compound classes. See Are Peptides Steroids?
Bottom line
"Are peptides natural?" has a clear chemistry answer. Peptides are defined by structure: amino acids joined by amide bonds [1][3]. Nature makes them on ribosomes [4][6], on NRPS assembly lines [7][8], and with dedicated enzymes such as those for glutathione [10]. Chemists make them on solid supports with SPPS [13][14][15]. "Natural" vs "synthetic" describes the route, not the molecule. The route mainly shapes which impurities need to be tested for [15].
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