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of protein folds offers insight into metabolic evolution
Life Sciences Editor
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by L. Brian Stauffer
|Professor of crop sciences Gustavo Caetano-Anollés and colleagues used data from two international compilations of genetic and
proteomic information and created a new database that links data sources into a new global network diagram of metabolic pathways.
CHAMPAIGN, Ill. —
Researchers at the University of Illinois have constructed the first
global family tree of metabolic protein architecture. Their approach
offers a new window on the evolutionary history of metabolism.
The study appears this week in the online edition of the Proceedings
of the National Academy of Sciences.
Their work relies on established techniques of phylogenetic analysis
developed in the past decade to plot the evolution of genes and organisms
but which have never before been used to work out the evolutionary history
of protein architecture across biological networks.
“We are interested in how structure evolves, not how organisms
evolve,” said professor of crop
sciences Gustavo Caetano-Anollés, principal researcher on
the study, which was co-written by graduate student Hee Shin Kim and
emeritus professor of cell and
developmental biology Jay E. Mittenthal. “We are using the
techniques of phylogenetic analysis that systematicists used to build
the tree of life, and we are applying it to a biochemical problem, a
systems biology problem.”
To get at the roots of protein evolution, the researchers examined metabolic
proteins at the level of their component structures: easily recognizable
folds in the proteins that have known enzymatic activities. These protein
domains catalyze a range of functions, breaking down or combining metabolites,
small molecules that include the building blocks of all life.
Their findings relied on a fundamental assumption: that the most widely
utilized protein folds (they looked at proteins in more than 200 species)
were also the most ancient.
“Protein architecture has preserved ancient structural designs
as fossils of ancient biochemistries,” the authors wrote.
The team used data from two international compilations of genetic and
proteomic information: the metabolic pathways database of the Kyoto
Encyclopedia of Genes and Genomes, and the Structural Classification
of Proteins database. They combined these two data sets with phylogenetic
reconstructions, or family trees, of protein fold architectures in metabolism.
They created a new database, called the Molecular Ancestry Network (MANET)
which links these data sources into a new global network diagram of
The researchers added color, representing evolutionary age, to their
diagrams of metabolic networks (for an example, see the purine metabolism
network in MANET).
The result is a multicolored mosaic of protein fold evolution. The mosaic
shows that modern metabolic networks – and even individual enzymes
– are composed of both very ancient and much more recent protein
“This mosaic is telling you that the new enzymes and old enzymes
are together performing side by side,” Caetano-Anollés
said. “In some cases in the same protein you have old domains
and new domains working together.”
This finding supports the hypothesis that protein architectures that
perform one function are often recruited to perform new tasks.
The new, global family tree of protein architecture also revealed that
many metabolic protein folds are quite ancient: These architectures
were found to be quite common in all the species of bacteria, animals,
plants, fungi, protists and archaea the researchers analyzed.
Of 776 metabolic protein folds surveyed, 16 were found to be omnipresent,
and nine of those occurred in the earliest branches of the newly constructed
“These nine ancient folds represent architectures of fundamental
importance undisputedly encoded in a genetic core that can be traced
back to the universal ancestor of the three superkingdoms of life,”
the authors wrote.
The analysis also found that the most ancient metabolic protein folds
are important to RNA metabolism, specifically the interconversion of
the purine and pyrimidine nucleotides that compose the core of the RNA
This discovery supports the hypothesis of an RNA world in which RNA
molecules were among the earliest catalysts of life. This idea is based
in part on the observation that RNA still retains many of its catalytic
capabilities, including the ability to make proteins. Gradually, according
to this theory, proteins began taking over some of the original functions
“The most ancient (protein) molecules were involved in the interconversion
of nucleotides. But they were not synthesizing them,” Caetano-Anollés
said. “We see that all the enzymes that were involved in purine
synthesis, for example, were very recent. Since these first proteins
benefited the formation of building blocks for the primitive RNA world,
it makes a lot of sense that we’ve found this origin encased in
Caetano-Anollés and Mittenthal are also affiliated with the Institute
for Genomic Biology.
This research was supported in part with funds from the U. of I. at
Urbana-Champaign, the Office of Naval Research and the National Science
Editor’s note: To reach Gustavo Caetano-Anollés, call 217-333-8172;