The xenortides (A-D) are a class of linear peptides isolated from the bacterium ''

Xenorhabdus nematophila ''Xenorhabdus'' is a genus of motile, gram-negative bacteria from the family of the Morganellaceae. All the species of the genus are only known to live in symbiosis with soil entomopathogenic nematodes from the genus ''Steinernema''. Although no ...

'',{{Cite journal, last=Lang, first=Gerhard, last2=Kalvelage, first2=Tim, last3=Peters, first3=Arne, last4=Wiese, first4=Jutta, last5=Imhoff, first5=Johannes F., date=2008-06-01, title=Linear and Cyclic Peptides from the Entomopathogenic Bacterium Xenorhabdus nematophilus, journal=Journal of Natural Products, volume=71, issue=6, pages=1074–1077, doi=10.1021/np800053n, pmid=18491867, issn=0163-3864 a symbiont of the

entomopathogenic nematode Entomopathogenic nematodes (EPN) are a group of nematodes (thread worms), that cause death to insects. The term ''entomopathogenic'' has a Greek origin, with ''entomon'', meaning ''insect'', and ''pathogenic'', which means ''causing disease''. T ...

Steinernema carpocapsae ''Steinernema carpocapsae'' is an entomopathogenic nematode and a member of the family Steinernematidae. It is a parasitic roundworm that has evolved an insect-killing symbiosis with bacteria, and kills its hosts within a few days of infection. ...

''. This class of compounds is known for their insect virulence and

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...

biological activities. The tryptamide containing compounds (xenortides B and D) show higher

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

than the phenylethylamides (xenortides A and C). The most biologically active compound was found to be xenortide B with a potency of less than 1.6 μM activity against ''

Trypanosoma brucei rhodesiense ''Trypanosoma brucei'' is a species of parasitic kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracel ...

'' (

sleeping sickness African trypanosomiasis is an insect-borne parasitic infection of humans and other animals. Human African trypanosomiasis (HAT), also known as African sleeping sickness or simply sleeping sickness, is caused by the species '' Trypanosoma b ...

) and ''

Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans and is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...

'' (

malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...

), however it is also the most toxic to mammalian cells which limits its viability as a treatment. The biosynthesis of xenortides A-D consists of two non-ribosomal peptide synthases (NRPS) coded by genes XndA and XndB, as well as upstream NADH flavin reductase, and a D-

aminopeptidase Aminopeptidases are enzymes that catalyze the cleavage of amino acids from the N-terminus (beginning), of proteins or peptides. They are found in many organisms; in the cell, they are found in many organelles, in the cytosol (internal cellular f ...

. The first NRPS (XndA) consists of a condensation,

adenylation Adenylylation, more commonly known as AMPylation, is a process in which an adenosine monophosphate (AMP) molecule is covalently attached to the amino acid side chain of a protein. This covalent addition of AMP to a hydroxyl side chain of the prote ...

methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...

, and

thiolation In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...

domain, and has been implicated for the loading of ''N''-methylleucine (xenortides A-B) or ''N''-methylvaline (xenortides C-D). The second NRPS (XndB) consists of a condensation, adenylation, methylation, thiolation, and terminal condensation domains. XndB has been implicated in elongation with ''N''-methylphenylalanine, as well as the final condensation of the enzyme-bound peptide with either

decarboxylated Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...

(xenortides A and C) or

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

(xenortides B and D), ending the

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

References

Dipeptides