Evolutionary history and metabolic insights of ancient mammalian uricases James T Kratzer cs 2014 PNAS 111:3763-8 doi org/10.1073/pnas.1320393111
We have a pseudo-gene for uricase that prevents a functional enzyme from being produced.
Our inability to convert highly insoluble UA into a more soluble molecule makes us vulnerable to disease.
How & why did apes lose this functional enzyme?
Did the progressive loss of uricase activity allow our ancestors to readily accumulate fat via the metabolism of fructose from fruits?
This adaptation may have provided our ancestors with an advantage when the energy-rich rain-forests of Europe & Asia were displaced by temperate forests end-Oligocene.
Uricase (an enzyme involved in purine catabolism) is found in all 3 domains of life.
Curiously, uricase is not functional in some organisms, despite its role in converting highly insoluble UA into 5-OH-iso-urate:
apes, incl.Hs, cannot oxidize UA:
multiple, independent evol.events led to the silencing (pseudo-genization) of the uricase-gene in ancestral apes.
Why would natural selection allow the accumulation of UA, despite the physiological consequences of crystallized mono-sodium urate, acutely causing liver/kidney damage, and chronically causing gout?
We have applied evol.models to understand the history of primate uricases, by resurrecting ancestral mammalian intermediates before the pseudo-genization events of this gene-family.
Resurrected proteins reveal:
ancestral uricases have steadily decreased in activity since the mammal LCA gave rise to descendent primate lineages.
- We could determine the 3D distribution of AA-replacements, as they accumulated during evol.history by crystallizing a mammalian uricase protein.
- Ancient & modern uricases were stably transfected into HepG2 liver-cells, to test:
did uricase pseudo-genization allow ancient frugivorous apes to rapidly convert fructose into fat?
- Pharmacokinetics of an ancient uricase injected in rodents suggest:
our integrated approach provides the foundation for an evol.engineered enzyme capable of treating gout, and preventing tumor lysis syndrome in human patients.
_____
Was uricase pseudo-genization (in Miocene apes?) for bridging the winter? and/or for making them fatter? MV@aat.io
All apes have subcutaneous fat, post-agric. Hs have much.
I don't understand those attempts of reverse engineering. From Wikipedia: "Reverse engineering (also known as backwards engineering or back engineering) is a process or method through which one attempts to
understand through deductive reasoning how a previously made device,
process, system, or piece of software accomplishes a task with very
little (if any) insight into exactly how it does so."
I mean, instead of trying to reverse engineer the past from one
particle of dust, why scientists don't take a look at the whole, and try
to understand the past from the situation that's going on on the planet Earth, as a whole? You will not understand our past from looking at one particle of dust, so what's the point?
He knows how the process goes today, what is it for, this tiny bit of reality, why he is trying to reconstruct our past by solely looking at
his little piece of reality that he is dealing with, that he is
researching? If he is interested in our past he has to look far beyond
his close field of research.
Evolutionary history and metabolic insights of ancient mammalian uricases James T Kratzer cs 2014 PNAS 111:3763-8 doi org/10.1073/pnas.1320393111
We have a pseudo-gene for uricase that prevents a functional enzyme from being produced.
Our inability to convert highly insoluble UA into a more soluble molecule makes us vulnerable to disease.
How & why did apes lose this functional enzyme?
Did the progressive loss of uricase activity allow our ancestors to readily accumulate fat via the metabolism of fructose from fruits?
This adaptation may have provided our ancestors with an advantage when the energy-rich rain-forests of Europe & Asia were displaced by temperate forests end-Oligocene.
Uricase (an enzyme involved in purine catabolism) is found in all 3 domains of life.
Curiously, uricase is not functional in some organisms, despite its role in converting highly insoluble UA into 5-OH-iso-urate:
apes, incl.Hs, cannot oxidize UA:
multiple, independent evol.events led to the silencing (pseudo-genization) of the uricase-gene in ancestral apes.
Why would natural selection allow the accumulation of UA, despite the physiological consequences of crystallized mono-sodium urate, acutely causing liver/kidney damage, and chronically causing gout?
We have applied evol.models to understand the history of primate uricases, by resurrecting ancestral mammalian intermediates before the pseudo-genization events of this gene-family.
Resurrected proteins reveal:
ancestral uricases have steadily decreased in activity since the mammal LCA gave rise to descendent primate lineages.
- We could determine the 3D distribution of AA-replacements, as they accumulated during evol.history by crystallizing a mammalian uricase protein.
- Ancient & modern uricases were stably transfected into HepG2 liver-cells, to test:
did uricase pseudo-genization allow ancient frugivorous apes to rapidly convert fructose into fat?
- Pharmacokinetics of an ancient uricase injected in rodents suggest:
our integrated approach provides the foundation for an evol.engineered enzyme capable of treating gout, and preventing tumor lysis syndrome in human patients.
_____
Was uricase pseudo-genization (in Miocene apes?) for bridging the winter? and/or for making them fatter? M...@aat.io
All apes have subcutaneous fat, post-agric. Hs have much.
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