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PubMed1992

On the evolution of functional secondary metabolites (natural products).

It is argued that organisms have evolved the ability to biosynthesize secondary metabolites (natural products) because of the selectional advantages they obtain as a result of the functions of the compounds. The clustering together of antibiotic biosynthesis, regulation, and resistance genes implies that these genes have been selected as a group and that the antibiotics function in antagonistic capacities in nature. Pleiotropic switching, the simultaneous expression of sporulation and antibiotic biosynthesis genes, is interpreted in terms of the defence roles of antibiotics. We suggest a general mechanism for the evolution of secondary metabolite biosynthesis pathways, and argue against the hypothesis that modern antibiotics had prebiotic effector functions, on the basis that it does not account for modern biosynthetic pathways.

Anti-Bacterial Agents↗
PubMedDate not supplied

Evolution of catalytic and regulatory sites in phosphorylases.

Glycogen phosphorylase (E.C.2.4.1.1) was the first enzyme shown to be regulated by allosteric effectors and by protein phosphorylation. Transcriptional control of bacterial phosphorylases further extends the range of regulatory mechanisms by which phosphorylases contribute to the control of carbohydrate metabolism. Despite their regulatory differences, all known phosphorylases share catalytic and structural properties and a strongly conserved pyridoxal-5'-phosphate binding site; this makes phosphorylases highly attractive for investigations into the evolution of regulatory mechanisms. The primary and tertiary structure of rabbit muscle phosphorylase has been determined completely. Recently, comparable amino acid sequences from plants and bacteria have been resolved. Here we report the sequence of 687 amino acids of Escherichia coli maltodextrin phosphorylase, deduced from a cloned malP gene sequence. Alignment of animal and bacterial phosphorylase sequences shows strong homology (48%) throughout 91% of the polypeptide chain enclosing the extrinsic catalytic region. Within this region, structural homology identifies a presumed phosphate-binding site from which the allosteric 5' AMP binding site of rabbit muscle phosphorylase might have developed. From the decreased alignment at the N-terminus and the presence of additional residues compared with bacterial phosphorylases, we conclude that the regulatory sequences that also carry the phosphorylation site in the muscle enzyme were joined to a presumed ancestral precursor gene by gene fusion after separation of the eukaryotic and prokaryotic lines of descent.

Adenosine Monophosphate↗
PubMed2026

Rapidly evolving aphid gall effector proteins exhibit saposin-like folds.

Many insects manipulate plants by injecting effector proteins. In one extreme example of this molecular "hijacking", Hormaphis cornu aphids inject bicycle proteins into Hamamelis virginiana (Witch Hazel), contributing to the development of novel organs called galls. Bicycle proteins share no amino acid sequence similarity with proteins of known function. Here, we report the crystal structures of two divergent bicycle proteins. Both proteins contain saposin-like folds: one with multiple disulfide bonds exhibits a helix swap; the other has no disulfide bonds and possesses two tandem domains. To explore the structural evolution of bicycle proteins, we predicted bicycle protein structures with Alphafold2 (AF2). While AF2 did not recover the two experimental structures using existing databases, it succeeded after we provided multiple sequence alignments (MSAs) containing protein sequences encoded in new genome sequences from closely related aphid species. Using this customized approach at scale, we generated 2400 high-confidence predictions for bicycle proteins from seven aphid species. This dataset revealed that bicycle proteins without cysteines are outliers in fold space and appear to have evolved from ancestral proteins with disulfide-bonded saposin-like folds. While all bicycle proteins contain predicted saposin-like folds, they display a vast diversity of structural and physicochemical properties. While this diversity thwarts prediction of conserved functions encoded in structure, it suggests that bicycle proteins have evolved to target diverse plant processes and/or to evade plant immune surveillance.

AlphaFold predictions↗
PubMed2026

Evolution of tumor subclones and T-cell dynamics underlie variable ibrutinib responses in Waldenström macroglobulinemia.

To elucidate the molecular basis underlying differential responses and resistance to ibrutinib in Waldenström macroglobulinemia (WM), we conducted a prospective phase 2 trial of ibrutinib monotherapy in treatment-naïve patients. A total of 74 sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multiomics. BM cells were segregated primarily into B-cell/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B cells/plasma cells identified 3 distinct evolutionary patterns: evolution (early clone contraction with late clone expansion and increasing genomic complexity), devolution (early clone expansion with late clone contraction and genomic simplification), and no evolution (stable clonal architecture). The evolution pattern was strongly associated with disease progression, whereas devolution correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström ibrutinib prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combination strategy. In parallel, GZMB+ CD8+ effector-memory T cells expanded after treatment in patients with progressive disease and coexisted with tumor evolution. These cells exhibited persistently impaired cytotoxic programs (eg, GNLY), a dedifferentiated memory-like state, elevated PDCD1 expression, and reduced T-cell receptor diversity. Together, this study provides, to our knowledge, the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM, introduces the WIP score as a predictive biomarker for treatment response, and identifies actionable tumor-intrinsic and immune mechanisms driving resistance. This trial was registered at www.ClinicalTrials.gov as NCT02604511.

Aged↗
PubMed1991

Antibiotic inhibition of group I ribozyme function.

The discovery of catalytically active RNA has provided the basis for the evolutionary concept of an RNA world. It has been proposed that during evolution the functions of ancient catalytic RNA were modulated by low molecular weight effectors, related to antibiotics, present in the primordial soup. Antibiotics and RNA may have coevolved in the formation of the modern ribosome. Here we report that a set of aminoglycoside antibiotics, which are known to interact with the decoding region of the 16S ribosomal RNA of Escherichia coli, inhibit the second step of splicing of the T4 phage-derived td intron. Thus catalytic RNA seems to interact not only with a mononucleotide and an amino acid, but also with another class of biomolecules, the sugars. Splicing of other group I introns but not group II introns was inhibited. The similarity in affinity and specificity of these antibiotics for group I introns and rRNAs may result from recognition of evolutionarily conserved structures.

Animals↗
PubMed2026

Phytoplasma-plant interactions: effector-mediated host reprogramming, hormonal crosstalk, metabolic alterations and plant-mediated vector manipulation.

Phytoplasmas are wall-less, phloem-restricted bacterial pathogens that infect over 1,000 plant species, causing substantial losses in agriculture, horticulture, and forestry worldwide. Despite their reduced genomes and limited metabolic autonomy, these obligate parasites colonize diverse hosts through secreted effector proteins that extensively reprogram plant development, metabolism, immune signalling, and vector interactions. Advances in genomics, transcriptomics, proteomics, metabolomics, and functional studies have substantially clarified the molecular basis of phytoplasma pathogenicity and symptom development. This review synthesizes current understanding of phytoplasma-plant interactions, covering phytoplasma biology, genome evolution, and the infection cycle across plant and insect vector hosts. We examine the molecular functions of key effectors, SAP11, SAP54/PHYL1, SAP05, TENGU, SWP1, and recently identified virulence factors, focusing on how they target host transcription factors, phytohormone networks, protein degradation pathways, and immune responses to promote colonization and disease progression. We further discuss how phytoplasma infection disrupts phytohormone signalling, primary and secondary metabolism, and developmental programs to produce characteristic disease symptoms, with particular attention to pathogen-induced changes in host volatiles and nutritional quality that alter vector behaviour and enhance transmission. Finally, we summarize insights from multi-omics studies and emerging management strategies, including CRISPR-based genome editing, RNAi, rapid molecular diagnostics, resistant cultivars, microbiome-based approaches, and sustainable vector control, and highlight key knowledge gaps and priorities for developing effective, environmentally sustainable phytoplasma disease management.

Phytoplasma↗
PubMed1989

Isolation and complete structure of the lymphocyte serine protease granzyme G, a novel member of the granzyme multigene family in murine cytolytic T lymphocytes. Evolutionary origin of lymphocyte proteases.

A cDNA clone that is closely related to the granule-associated serine proteases of cytolytic T lymphocytes (CTL), called granzymes A-F, was isolated from a CTL expression library. The encoded serine protease, granzyme G, shows 70%-89% nucleotide identities to the granzymes C-F and, like those, consists of 228 amino acids preceded by the short propeptide Glu-Glu and a 18 residue long signal peptide. Granzyme G was identified by amino-terminal sequence analysis as a correctly processed and sorted protein stored in lysosome-like granules. The phylogenetic history of the granzyme multigene family was reconstructed by two tree-making methods and by Southern blot analyses of human, rat, and mouse DNA. Our results indicate differences in the evolutionary pathway between these species. The murine granzymes C-G descended from a progenitor present at the time of mammalian radiation. Granzyme C branched off first after the primate-rodent split and was involved in a recombination event with granzyme B before the rat-mouse divergence. Granzymes D and E have diverged after the mouse-rat speciation. However, no experimental evidence for the existence of a granzyme C-D-E-F-G equivalent was found in humans, and loss of the ancestral gene in the primate lineage is discussed. In view of the species differences in the number of granzyme gene copies during recent evolution, we propose that the murine granzymes B-G play several distinct roles in CTL-mediated effector functions as a response to quite recent changes of the biochemical environment.

Amino Acid Sequence↗
PubMed2025

Evolutionary and Functional Analysis of Caspase-8 and ASC Interactions to Drive Lytic Cell Death, PANoptosis.

Caspases are evolutionarily conserved proteins essential for driving cell death in development and host defense. Caspase-8, a key member of the caspase family, is implicated in nonlytic apoptosis, as well as lytic forms of cell death. Recently, caspase-8 has been identified as an integral component of PANoptosomes, multiprotein complexes formed in response to innate immune sensor activation. Several innate immune sensors can nucleate caspase-8-containing PANoptosome complexes to drive inflammatory lytic cell death, PANoptosis. However, how the evolutionarily conserved and diverse functions of caspase-8 drive PANoptosis remains unclear. To address this, we performed evolutionary, sequence, structural, and functional analyses to decode caspase-8's complex-forming abilities and its interaction with the PANoptosome adaptor ASC. Our study distinguished distinct subgroups within the death domain superfamily based on their evolutionary and functional relationships, identified homotypic traits among subfamily members, and captured key events in caspase evolution. We also identified critical residues defining the heterotypic interaction between caspase-8's death effector domain and ASC's pyrin domain, validated through cross-species analyses, dynamic simulations, and in vitro experiments. Overall, our study elucidated recent evolutionary adaptations of caspase-8 that allowed it to interact with ASC, improving our understanding of critical molecular associations in PANoptosome complex formation and the underlying PANoptotic responses in host defense and inflammation. These findings have implications for understanding mammalian immune responses and developing new therapeutic strategies for inflammatory diseases.

Caspase 8↗
PubMed2026

Diverse haplotypes at a complex Solanum americanum locus confer resistance to Phytophthora infestans and P. capsici.

Plants encounter diverse pathogens and have evolved a two-layered innate immune system to detect pathogen molecules and activate defense mechanisms that restrict infection. Most cloned plant Resistance (R) genes encode NLR immune receptors. NLR genes are often found in clusters of paralogs with sequence and copy number variation; whether these NLR clusters evolve in response to single or multiple pathogens has been unclear. We report here the isolation of a Phytophthora capsici resistance gene, Rpc2, along with a novel P. infestans resistance gene, Rpi-amr5, from two Solanum americanum accessions. These orthologous genes reside in the Rpi-amr1 cluster, which has previously been associated with resistance to P. infestans. By screening RXLR effector libraries of P. infestans and P. capsici, we identified multiple effectors recognised by both NLRs. Our findings highlight the complexity of NLR clusters and evolution driven by interactions with multiple pathogens. This work will underpin efforts to elevate resistance against Phytophthora pathogens and enhances our understanding of NLR evolution.

Journal Article↗
PubMed1988

Evolution of neurotransmitter receptor systems.

The presence of hormones, neurotransmitters, their receptors and biosynthetic and degradative enzymes is clearly not only associated with the present and the recent past but with the past several hundred million years. Evidence is mounting which indicates substantial conservation of protein structure and function of these receptors and enzymes over these tremendous periods of time. These findings indicate that the evolution and development of the nervous system was not dependent upon the formation of new or better transmitter substances, receptor proteins, transducers and effector proteins but involved better utilization of these highly developed elements in creating advanced and refined circuitry. This is not a new concept; it is one that is now substantiated by increasingly sophisticated studies. In a 1953 article discussing chemical aspects of evolution (Danielli, 1953) Danielli quotes Medawar, "... endocrine evolution is not an evolution of hormones but an evolution of the uses to which they are put; an evolution not, to put it crudely, of chemical formulae but of reactivities, reaction patterns and tissue competences." To also quote Danielli, "In terms of comparative biochemistry, one must ask to what extent the evolution of these reactivities, reaction patterns and competences is conditional upon the evolution of methods of synthesis of new proteins, etc., and to what extent the proteins, etc., are always within the synthetic competence of an organism. In the latter case evolution is the history of changing uses of molecules, and not of changing synthetic abilities." (Danielli, 1953). Figure 4 outlines a phylogenetic tree together with an indication of where evidence exists for both the enzymes that determine the biosynthesis and metabolism of the cholinergic and adrenergic transmitters and their specific cholinergic and adrenergic receptors. This figure illustrates a number of important points. For example, the evidence appears to show that the transmitters and their associated enzymes existed for a substantial period before their respective receptor proteins. While the transmitters and enzymes appear to exist in single cellular organisms, there is no solid evidence for the presence of adrenergic or cholinergic receptors until multicellular organisms where the receptors appear to be clearly associated with specific cellular and neuronal communication (Fig. 4). One can only speculate as to the possible role for acetylcholine and the catecholamine in single cell organisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

What are antibiotics? Archaic functions for modern activities.

Secondary metabolites are proposed to have played important roles in the evolution of the reactions of living forms on earth, in effecting and modulating reactions during biochemical evolution by chemical and structural interaction with 'receptor' sites in primitive macromolecular templates. For example, in the evolution of the translation system, as the polymerizing reactions became more complex and proteins became involved, the low molecular-weight effectors were functionally replaced by polypeptides, but retained their ability to interact with receptor sites in nucleic acids and proteins. Many of these low molecular-weight effectors now play a different role, that of antagonists, by interacting with the original receptor sites in macromolecular structures; this explains their contemporary activity as antibiotics.

Animals↗
PubMed1989

The Drosophila gene coding for the alpha subunit of a stimulatory G protein is preferentially expressed in the nervous system.

In mammals, the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gs alpha) functions to couple a variety of extracellular membrane receptors to adenylate cyclase. Activation of Gs alpha results in the stimulation of adenylate cyclase and an increase in the second messenger cAMP. A 1.7-kilobase cDNA has been identified and characterized from Drosophila that codes for a protein 71% identical to bovine Gs alpha. The similarity is most striking in the regions thought to be responsible for the interactions with receptors and effectors, suggesting that the basic components of this signal-transduction pathway have been conserved through evolution. RNA blot hybridization and DNA sequence analysis suggest that a single transcript, expressed predominantly in the head, is present in Drosophila. In situ hybridization studies indicate that the Drosophila Gs alpha transcript is localized primarily in the cells of the central nervous system and in the eyes.

Amino Acid Sequence↗
PubMed1992

Evolution of the mammalian G protein alpha subunit multigene family.

Heterotrimeric guanine nucleotide binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins. The multigene family of G protein alpha subunits, which interact with receptors and effectors, exhibit a high level of sequence diversity. In mammals, 15 G alpha subunit genes can be grouped by sequence and functional similarities into four classes. We have determined the murine chromosomal locations of all 15 G alpha subunit genes using an interspecific backcross derived from crosses of C57BL/6J and Mus spretus mice. These data, in combination with mapping studies in humans, have provided insight into the events responsible for generating the genetic diversity found in the mammalian alpha subunit genes and a framework for elucidating the role of the G alpha subunits in disease.

Animals↗
PubMed2026

Experimental evolution reveals genetic routes for adaptive loss of the antibacterial type VI secretion system.

The type VI secretion system (T6SS) is a contractile nanomachine used by Gram-negative bacteria to deliver effector proteins into target cells, contributing to both interbacterial competition and pathogenesis. Although T6SS gene clusters are present in recently isolated commensal and pathogenic Escherichia coli strains, they are absent from classical laboratory strains that have been propagated for decades in pure cultures, suggesting that T6SS can be lost in the absence of competition. Here, we combined experimental evolution with whole-genome sequencing to track the fate of the enteroaggregative Escherichia coli (EAEC) Sci1 T6SS during competition with either T6SS-susceptible or T6SS-immune bacteria. After ∼640 generations, T6SS activity was largely maintained during competition with T6SS-susceptible bacteria, whereas ∼90% of clones evolved with T6SS-immune bacteria lost or attenuated T6SS activity through diverse mutations within the sci1 promoter, essential T6SS structural genes, or the rfaH transcriptional antiterminator. We identified two RfaH-binding ops elements within the sci1 cluster, revealing antitermination as a regulatory element of EAEC T6SS transcription, which is conserved among Enterobacteriaceae. Our findings highlight how experimental evolution can reveal the selective forces shaping T6SS maintenance and identify new regulatory components controlling its activity.

Journal Article↗
PubMed1991

Evolution of the complement system.

The ancestral form of the alternative pathway of complement activation probably originated as a primitive independent immune system. Subsequent evolution of an adaptive immune response drove the specialization of the classical pathway to connect antibody-mediated nonself recognition to the complement-dependent effector mechanisms. In this article Timothy Farries and John Atkinson consider how the contemporary complexity arose by a succession of credible alterations at the genetic level, and the selective advantages provided at each step.

Biological Evolution↗
PubMed2025

Diversification of an emerging bacterial plant pathogen; insights into the global spread of Xanthomonas euvesicatoria pv. perforans.

Emerging and re-emerging plant diseases continue to present multifarious threats to global food security. Considerable recent efforts are therefore being channeled towards understanding the nature of pathogen emergence, their spread and evolution. Xanthomonas euvesicatoria pv. perforans (Xep), one of the causal agents of bacterial spot of tomato, rapidly emerged and displaced other bacterial spot xanthomonads in many tomato production regions around the world. In less than three decades, it has become a dominant xanthomonad pathogen in tomato production systems across the world and presents a compelling example for understanding diversification of recently emerged bacterial plant pathogens. Although Xep has been continuously monitored in Florida since its discovery, the global population structure and evolution at the genome-scale is yet to be fully explored. The objectives of this work were to determine genetic diversity globally to ascertain if different tomato production regions contain genetically distinct Xep populations, to examine genetic relatedness of strains collected in tomato seed production areas in East Asia and other production regions, and to evaluate variation in type III secretion effectors, which are critical pathogenicity and virulence factors, in relationship to population structure. We used genome data from 270 strains from 13 countries for phylogenetic analysis and characterization of type III effector gene diversity among strains. Our results showed notable genetic diversity in the pathogen. We found genetically similar strains in distant tomato production regions, including seed production regions, and diversification over the past 100 years, which is consistent with intercontinental dissemination of the pathogen in hybrid tomato production chains. Evolution of the Xep pangenome, including the acquisition and loss of type III secreted effectors, is apparent within and among phylogenetic lineages. The apparent long-distance movement of the pathogen, together with variants that may not yet be widely distributed, poses risks of emergence of new variants in tomato production.

Xanthomonas↗
PubMed1991

A cellular logic for G protein-coupled ion channel pathways.

A vast array of cellular signal transduction processes arise from combinations of many different types of agonists, receptors, effectors, and coupling molecules such as heterotrimeric G proteins or protein kinases that connect receptors to effectors. Receptors, effectors, G proteins, and kinases are being newly identified at bewildering speeds and in the process it seems that our understanding of how cells respond to specific stimuli may have diminished just as we lose sight of the forest when we are buried in the trees. Evolution would suggest that there may be a logic to the response provoked by a given stimulus and, using our recently acquired knowledge of G protein pathways between receptors and ion channel effectors, I will attempt to decipher what the underlying logic might be.

Animals↗