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.

On 25.4.2022. 5:08, DD'eDeN aka note/nickname/alas_my_loves wrote:
> 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.

--
https://groups.google.com/g/human-evolution
human-evolution@googlegroups.com

Mario Petrinovic wrote:

> 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.

The problem is that DNA simply does not work the way they insist that it
must.

I hate to keep harping on it but, again, look at Mungo Man. BILLIONS of
people trace their ancestry to the same group that gave rise to him,
long before any "Mitochondrial Eve," and it would be impossible to know
this, going by their interpretations of genetic evidence, if it weren't for a
lucky mutation copying mtDNA over to Chromosome 11.

He's not unique.

It's simple: If 5 people have [Gene A] and 2 people have [Gene B], all
things being equal, chances are that [Gene B] will vanish within so many
generations.

There's an often repeated claim that, looking at anyone who was alive 4
or 5 thousand years ago (I forget the exact figure), either EVERYONE today
is related to them or nobody is.

I saw another study that claimed it would only take a thousand years
before any genetic trace of you was gone from your descendants...

Both of these claims are statistical, not necessarily pure fact but, if it's a
statistical probability after a few thousand years then what happens
after 1.7 million years?

Everything we know, applied to paleo anthropology, tells us it's full of crap.
That, the DNA can't tell us the things they are pretending to see. You don't
have to be brilliant in order to debunk them, you just have to be consistent.

...we just have to stop throwing away what we know & accept when
looking at DNA.

-- --

https://jtem.tumblr.com/post/682443470330298368

On Sunday, April 24, 2022 at 11:08:45 PM UTC-4, DD'eDeN aka note/nickname/alas_my_loves wrote:
> 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.

Fructose & uricase metabolism

https://onlinelibrary.wiley.com/doi/full/10.1111/joim.12993