Gene duplication and the evolution of moonlighting proteins

Espinosa-Cantú, Adriana; Ascencio, Diana; Barona‐Gómez, Francisco; DeLuna, Alexander

doi:10.3389/fgene.2015.00227

Cited by 86 publications

(63 citation statements)

References 67 publications

(71 reference statements)

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“…I propose that the defective lipoate ligase activity of LIPT1 is a remnant of enzyme evolution that has long misled the field and posit that the relevant activity of the protein is amidotransfer, the reaction catalyzed by the B. subtilis and L. monocytogenes LipL proteins. In recent years, a concept of enzyme evolution called moonlighting has received much support (155)(156)(157)(158). A protein can acquire a second (moonlighting) function without concomitantly losing its original function.…”

Section: Conclusion and A Unifying Hypothesismentioning

confidence: 99%

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

Cronan

2016

Microbiol Mol Biol Rev

128

137

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SUMMARYAlthough the structure of lipoic acid and its role in bacterial metabolism were clear over 50 years ago, it is only in the past decade that the pathways of biosynthesis of this universally conserved cofactor have become understood. Unlike most cofactors, lipoic acid must be covalently bound to its cognate enzyme proteins (the 2-oxoacid dehydrogenases and the glycine cleavage system) in order to function in central metabolism. Indeed, the cofactor is assembled on its cognate proteins rather than being assembled and subsequently attached as in the typical pathway, like that of biotin attachment. The first lipoate biosynthetic pathway determined was that ofEscherichia coli, which utilizes two enzymes to form the active lipoylated protein from a fatty acid biosynthetic intermediate. Recently, a more complex pathway requiring four proteins was discovered inBacillus subtilis, which is probably an evolutionary relic. This pathway requires the H protein of the glycine cleavage system of single-carbon metabolism to form active (lipoyl) 2-oxoacid dehydrogenases. The bacterial pathways inform the lipoate pathways of eukaryotic organisms. Plants use theE. colipathway, whereas mammals and fungi probably use theB. subtilispathway. The lipoate metabolism enzymes (except those of sulfur insertion) are members of PFAM family PF03099 (the cofactor transferase family). Although these enzymes share some sequence similarity, they catalyze three markedly distinct enzyme reactions, making the usual assignment of function based on alignments prone to frequent mistaken annotations. This state of affairs has possibly clouded the interpretation of one of the disorders of human lipoate metabolism.

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Section: Conclusion and A Unifying Hypothesismentioning

confidence: 99%

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

Cronan

2016

Microbiol Mol Biol Rev

128

137

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“…Thus, genetic redundancy fortifies natural selection for cell survival (drug resistance) [162]. Combination therapy and synthetic lethality strategies are currently being explored to transform cancer phenotypes to lethal (apoptotic) phenotypes [66,157,160,162]. Genetic background assessments on a caseby-case basis may improve clinical efficacy in such pursuits.…”

Section: Molecular Connections Between Lc and Pcmentioning

confidence: 99%

“…Paralogous genes that functionally compensate one another implies their importance to cell survival, and fortifies Darwinian selection by reproductive fitness [155,156]. Genetic redundancy does not necessarily imply functional redundancy, as paralogous gene products may have divergent functions elsewhere in the cell (e.g., moonlighting proteins) [156][157][158]. The crosstalks of Hh, NOTCH, WNT and CXCR4 functionally succeed in proliferation of cancer phenotypes and variations thereof [80,159].…”

Section: Molecular Connections Between Lc and Pcmentioning

confidence: 99%

“…Despite treatment with pathway inhibitors, LC and PC phenotypes and variations thereof continue to progress and metastasize [80,160]. The 'synthetic lethality' approach aims to thwart oncogene addiction and panresistance -fortified disease progression through the exploits of functional redundancy [157,160]. For example, CXCR4, NOTCH, and WNT pathways can turn on Hh downstream targets.…”

Section: Molecular Connections Between Lc and Pcmentioning

confidence: 99%

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The Molecular Connections between Lung and Pancreatic Cancer Metastases: are we not seeing the Forest for the Trees?

Wilson¹

2017

JCPCR

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Metastases to the pancreas are rare at 1-2%. Among primaries metastasizing to the pancreas, lung cancer (LC) is frequently the culprit. Metastases to the lung from pancreatic cancer (PC) are significantly more common at about 45%, presenting striking differences in cancer behavior. There are conflicting reports regarding cancerogenicity and metastatic incidence between the lung and pancreas. Therefore, this review takes a fresh look at lung and pancreatic cancer behavior. Secondary metastases to the lung and pancreas are often indistinguishable from LC and PC primaries, and the seed and soil hypothesis is not always congruous with clinical interpretation of disease course. Sometimes single "seed" dissemination is thought to occur at the preneoplastic stage without any evidence of tumor invasion. Metastatic growth may become dormant, manifesting years later as cancer of unknown primary (CUP). Interestingly, CUPs are discovered to originate most frequently from LC and PC primaries at autopsy. The lung and pancreas are morphologically related through endoderm-level morphogenesis. The molecular basis of cancer regularity between them involves developmental signaling pathways including HEDGEHOG, NOTCH, WNT, and CXCL12/CXCR4, an evolving genetic background, and regulatory tumor-stromal interactions. Perhaps biomarkers that explain the regularity between them have been documented -as we peruse the bioscience literature for information, we may be reading through viable biomarkers and solutions and not seeing the forest for the trees. On the other hand, perhaps more research is warranted to explain cancer behavior between the lung and pancreas. Observations in this review provide a framework on which to extract clues for future work regarding organspecific metastasis between the lung and pancreas.

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“…However, the rapid accumulation of mutations can also result in partial or complete functional 7 divergence between the two copies. This may create a selective advantage due to increased functional repertoire 8 through neo-functionalization, greater efficiency and control through sub-functionalization, and possibly resistance to 9 deleterious mutations through vestigial functional overlap (functional moonlighting) [3][4][5], leading to retention of 10 both diverged copies (paralogs). After subsequent speciation events give rise to diverged genomes (species), each of 11 those genomes contains a gene descended through speciations from each paralog in the ancestral genome ( Figure 1).…”

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confidence: 99%

ASPEN: A methodology for reconstructing protein evolution with improved accuracy using ensemble models

Sloutsky

Naegle

2017

Preprint

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Mapping the history of gene duplications which gave rise to a protein family encoded in a genome (a set of paralogs) can be critical to understanding how those proteins function in their host cells today. However, since each member of a family is recapitulated in the genomes of related species (a set of orthologs), selection of sequences to be included in the history reconstruction is non-trivial. Reconstruction is extremely sensitive to the choice of sequences, which is deeply problematic given no mechanism exists for assessing the accuracy of individual reconstructions. Here, we capitalize on the variability of phylogenetic tree reconstruction to selected input sequences, by subsampling from the available ortholog sequences of a protein family to create an ensemble of trees, which explores the space of plausible tree topologies. We hypothesize that the most consistent topological features across an ensemble are more likely to be true and propose a tree reconstruction algorithm (ASPEN) based on this hypothesis. We simulate 600 protein families over known phylogenies, with varying branch lengths, and compare the accuracy of ASPEN reconstructions to those of traditional phylogeny inference methods. We find that ASPEN trees are more accurate than trees reconstructed traditionally. Additionally, we develop an observable metric calculated form subsampling, reconstruction Precision, for assessing the likely accuracy of a traditional, single-alignment all-sequence reconstruction of the divergence history for a set of paralogs. Together these findings suggest that an ensemble of imperfect reconstructions can provide more accurate insight than any individual reconstruction.

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Gene duplication and the evolution of moonlighting proteins

Cited by 86 publications

References 67 publications

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

The Molecular Connections between Lung and Pancreatic Cancer Metastases: are we not seeing the Forest for the Trees?

ASPEN: A methodology for reconstructing protein evolution with improved accuracy using ensemble models

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