Attached is Larry Moran’s exit exam for biochemistry and molecular biology. Exit Exam for Biochemistry.
I probably will not get a lot of these right on the first try, but it is a good learning experience. When I don’t know the answer, I can look it up, so this is a good chance to review important concepts.
I will provide answers I think Professor Moran wants students to give, and then I’ll provide my own answers which I think he might dock points for if he were grading. I always try to give the answer the professor is expecting even if I disagree. It shows that I am trying to understanding of what he was trying to teach. It’s not a confession of belief on my part.
For example:
21.How much of your genome is functional?
Answer I think Larry is expecting:
10%, because of the limits mutational load imposes on a genome the size of a human’s and their reproductive excess. But even the 10% number is likely high since the Muller Limit of 1 mutation/person/generation might allow even less than 10% function for the human genome.
My answer:
don’t know, neither does anyone else
Smart Arse Answer:
10% despite the fact ENCODE says 80% because ENCODE are a bunch of “ignoramuses, crooks generating piles of excrement” according to Dr. Moran’s colleague Dan Graur.
Some questions stumped me like:
3.Why can’t you have a lipid monolayer?
Eh? Doesn’t a micelle “layer” count as having a mono layer? Guess not.
I guess the answer is the hypdrophobic tails of the amphipathic phospholipids will generally tend to attach to each other, therefore such lipids are more likely to spontaneously form and remain in the bilayer configuration. But a micelle monolayer associates the hydrophobic tails too, doesn’t it?
Another Question:
17.Why are the amino acids sequences of a typical enzyme different in mice and humans?
Answer I think Larry is expecting:
Enzymatic polymorphisms occur because in many cases differences in amino acids at certain locations (such as those outside the active site) do not require high specificity. Function can be sustained under a variety of different amino acids in certain positions, thus random mutations in the process of common descent with modification will generate polymorphisms in positions which do not affect enzymatic function.
My answer:
The polymorphisms can be due to different functional constraints such as those resulting from necessary DNA binding motifs and microRNA regulatory targets that result in non-synonymous amino acid differences, Also there are possible different functionally significant post-translationtional modifications that are amino acid specific which have not yet been detected due to the difficulty of actually measuring such modifications in all possible contexts.
Another question:
30.Why do eukaryotic genes have introns?
My textbook non-answer:
Prokaryotes have introns, but no spliceosomal introns like Eukaryotes, so I believe Dr. Moran is referring to spliceosomal introns. Honestly, I don’t recall I’ve ever gotten a good answer from evolutionists. I don’t think Lehninger even attempted an answer. Since I don’t have copy of Larry’s textbook, but only Lehninger’s, can I be excused until I can get a hold of Larry’s book? 🙂
My answer:
For multicellular eukaryotes, the introns allow more diversity in gene expression between cell types as they can act as parts of robotic arms in 3D space to position regulatory and transcriptional machinery onto genes. This can happen from introns in other gene in a cis or even trans chromosomal context. Because of histones, chromatin complexes that contain introns are also capable of information processing and storage allowing them to be manipulated according to their histone chemical state to do gene regulation in a 3D manner as shown here:
For unicellular eukaryotes, I don’t have a good answer at this time (and neither do I think anyone else does), except God wanted to make other KINDS of Rube Goldberg machines.
The role of introns that are transcribed or excised is still not well understood. Primate specific Alus are indicated to use introns to make circular dsRNAs that appear important in alternative splicing. Until high throughput methods emerge to sequence proteomes in large scale and detect alternative splices, post translational modifications, glyco conjugation, etc. the role of introns may not be evident to the extent they may effect these (especially alternative splicing).
Papers on the function of introns have been published that list even more roles for introns.
But here is the rest of the exam. I’ll put some answers out in the comment section. Some answers will have to wait until after I finish this semester’s biochemistry evening class at the NIH. 🙂 Anyone else can weigh in with their answers.
1.Where do non-photosynthetic chemoautotrophs get their energy?
2.What is a typical Gibbs free energy change for a metabolic reaction inside a cell?
3.Why can’t you have a lipid monolayer?
4.Why is DNA supercoiled?
5.Which pathway evolved first; glycolysis or glucoenogenesis?
6.Why is methionine an essential amino acid in humans but glutamate is not?
7.Can humans fix carbon dioxide?
8.What are the end products of photosynthesis?
9.How do you create a protonmotive force?
10.How do some species survive without a citric acid cycle?
11.Why is some DNA replication discontinuous?
12.Why does E. coli need so many molecules of RNA polymerase?
13.Why is the ribosome so big and complex?
14.Why are there six codons for arginine but only one for tryptophan?
15.Why is Levinthal’s paradox not a paradox?
16.Why does DNA rich in G/C denature at a higher temperature than A/T-rich DNA?
17.Why are the amino acids sequences of a typical enzyme different in mice and humans?
18.If protein folding is spontaneous then why do cells need chaperones?
19.Why do acids like acetic acid and formic acid have different pKas?
20.Why did you need to learn about the Michaelis-Menten equation?
21.How much of your genome is functional?
22.Why is ATP not an effective allosteric regulator of enzyme activity?
23.What is flux?
24.Why isn’t it correct to say that ATP is an energy-rich compound?
25.What was the point of learning about reduction potentials?
26.Why are transcription and translation separated in eukaryotic cells?
27.Why did it take so long to evolve an oxygen evolving complex in photosynthesis?
28.Why is fat better than sugar for storing energy?
29.Why do we need cholesterol?
30.Why do eukaryotic genes have introns?
31.What’s the point of homologous recombination?
32.How can bacteria survive without mitochondria?
Mung,
There still wouldn’t be a why in evolution. Other than, it didn’t kill them enough to prevent it.
I read the question to be about humans [you], not extremophiles. Why is why my answer appealed to the lung.
stcordova,
I’m only guessing, but my guess would be that ATP is too globally utilised a molecule to be an effective allosteric regulator in general. But I don’t see anything precluding it from regulating certain key reactions. ATP levels need controlling somehow. I believe PFK is regulated by ATP/AMP ratio, among other things.
My biochemistry is 35 years old, though.
Moved some comments to guano. Moderation issues: discuss them in the appropriate thread. PM me if you have a particular issue you feel is being overlooked.
Or you read the comments first, then made up this self-congratulating story. In fact having interacted with you for some time now, I strongly suspect this is what really happened.
First version of question #3:
After that was successfully challenged by Bryan we have the 2nd version of question #3:
Ok, here is my creationist-pretending-to-be-an-evolutionist answer:
OK that was my creationist-pretending-to-be-an-evolutionist-on-the-exam answer so I can pass the exam.
My smart arse true answer:
🙂
stcordova,
This is you learning about biochemistry, is it?
Allan Miller,
IIRC, ATP levels just don’t vary enough to make it a good effector. The “thing that Sal was missing” was right there in the passage he quoted, thinking it was a refutation:
ADP is an useful effector. And AMP, of course, is kick-ass!
It entertains me no end that Sal can read and quote all this stuff without any apparent comprehension.
“…throughout the 20th century, the lipids have been somewhat overlooked molecules.”
“…it is unlikely that it is written in the genome how a cell and its various parts are assembled from the molecular building blocks. The information contained in the genome is, in this sense, not complete…”
Forming the Essential Template for Life: The Physics of Lipid Self-Assembly
https://en.wikipedia.org/wiki/Lipidomics
I know, right? It makes it difficult for me to stay up with him.
“Extended two-dimensional lipid monolayers as shown in figure 18.1a are easily formed by spreading a lipid solution at an air/water interface.”
Forming the Essential Template for Life: The Physics of Lipid Self-Assembly
3. Why can’t you have a lipid monolayer?
I think it’s another trick question. Aren’t lipid bilayers composed of two monolayers?
DNA_Jock,
Not sure about that. They don’t vary much because it is an allosteric regulator of its own production – eg PFK! Obviously there is a two-way effect with ATP and AMP/ADP working in opposite directions.
My slightly revised guess is that a cofactor can’t also be a regulator – you need substrates or products rather than the energy source. But for certain pathways, ATP is a product, so surely can regulate. But I am curious about the official answer to this.
Write a paper.
No, it’s Sal knowing he’s right all along and finding out to what degree those preexisting beliefs are supported by reality.
Mung,
That’s a trick answer. A bilayer is just one monolayer, folded, in the same way a folded sheet of paper is still just one sheet. That’s another trick answer. But gradually, the biochemical picture emerges from the semantic gotchas.
Thanks Allan. 🙂
Hugs.
You’re really degrading my ability to trust the authorities. 🙁
Mung,
If biochemical understanding rises through Gotchas rather than a more direct route, due to a reverse argument from authority (eg: Moran scorns ID so let’s pick the bones out of his every sentence), it is probably better than nothing.
.
Why do you think ATP levels in the reaction catalized by Phosphofurctokinase1 doesn’t vary much? Did it occur to you it’s partly because ATP is acting as it’s own allosteric regulator. Even Allan Miller could see through your folly.
.
On the contrary, you’re just entertaining yourself with your own misunderstandings. Do you enjoy publicly embarrassing yourself like this? Oh, yeah, from the guy who said of thermodynamics.
Other people have had issues with Larry’s Question 22:
I posted here:
https://sandwalk.blogspot.com/2017/01/the-exit-exam-for-biochemistry-and.html?showComment=1485785997450#c634529130088905557
Tages Haruspex’s comment is here:
https://sandwalk.blogspot.com/2017/01/the-exit-exam-for-biochemistry-and.html?showComment=1485272186120#c150408545014910429
stcordova,
Even that deadbeat? Good grief! 😉
I think matters may be more subtle than you realise, nonetheless, Sal.
Wikipedia on PFK:
The key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes PFK is activated by fructose 2,6-bisphosphate. The purpose of fructose 2,6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin.
The question is missing some qualifiers.
Oh, I agree. I’m not saying Larry is wrong, he obviously has something in mind. I”m trying to goad him into explaining why ATP is not a good allosteric regulator. He’s has my curiosity going now.
Because the level of ATP is extremely tightly regulated by multiple mechanisms.
Yes, it did occur to me, and under normal conditions the “partly” is miniscule. That
s why ATP is not an <strong>effective</strong> allosteric regulator. As Allan noted, its the ratio of ATP/AMP that regulates PFK. And as I said,Do you understand why?
DNA_Jock,
Without ATP synthase you wouldn’t have ATP. And you don’t have a mechanism capable of producing ATP synthase
Okay, so I just
learned somethingabout how to achieve <PRE> in this environment:use the
apostrophekey, rather than single quotesAnswer I think Larry wants:
My answer:
stcordova,
Wha…? If there are 6 arginine codons but only 1 for tryptophan, of course Arg would be more abundant than Trp – even in random transcripts …
Take a 6 sided die. With my foreknowledge mind powers I predict that there will be more 1-5 throws than 6. Go …
…
I know, right? How did I do it? I should be on the telly.
Tryptophan is thought to be the last amino acid to be included in the genetic code. So both the fact that it is only coded for by one codon, and it’s low frequency in proteins, is explained by it’s relatively late evolutionary arrival to the scene.
Another way evolution can make sense of the low frequency of Trp in proteins is that with only 1 codon, it has a comparatively low chance of being produced by mutation.
That means of all the ways a given codon can mutate, all else being equal the chance the mutation will result in a switch to the Trp codon is 1 in 64, whereas for all the other amino acids the chances are 2-3-4 times as much. It might be even higher if things like substitution bias are included.
http://www.tiem.utk.edu/~gross/bioed/webmodules/aminoacid.htm
Rumraket,
First part right, 2nd part not, I’d say. With only 1 codon, mutations (and misreads) from Trp are more likely, more than balancing the benefit of avoiding mutation to.
yeah, TRP would be more fragile, not less. BUT, despite creationist beliefs that this sequence And Only This Sequence can produce this essential protein, making it so hard for a search to locate, the fact is there are lots of substitutions you can make that change essentially nothing. If you are looking at a protein sequence, and it’s a decent-size protein, and you see a TRP, almost always you can swap out the TRP for phenylalanine, PHE, and run it through some e coli to make the protein, and get a mutant with essentially identical conformation and stability. Just to give one example. Or glycine to leucine. Or serine to cysteine.
in other words those unique sequence probability calculations creationists love are garbage.
https://en.wikipedia.org/wiki/Conservative_mutation
Wouldn’t it be both? The fact that it only has 1 codon means that it is both less likely of being produced by spontaneous mutation from something else, and it’s more likely of mutating away again even if a Trp codon is spontaneously produced?
Related to Larry’s exam, there was a brief exchange that I think is valuable to both sides.
[I don’t know why Larry’s interface calls me liarsfordarwin, that’s my blog, not my handle. My handle is stcordova)]. I’m leaving it that way for now because it ended up sounding so funny:
Larry’s Response:
and then my counter response:
Rumraket,
If Trp has any role, 1 codon means that all Trp positions are mutationally sensitive. Redundancy is beneficial in that it reduces that. The optimal redundancy would be an even spread, not everything cramming one poor assignment into a corner. .
That all depends on the tRNAs.
I’m still searching for where your statistical mechanics textbook relies on it. Perhaps you can give me a page number?
Well, that may be owing to the exam question, not really my answer because strictly speaking this isn’t subject to direct verification anyway!
We have substantial nucleotide bias in various species and then we also have codon bias. So in light of this, it looks more like the frozen accidents theory has an advantage.
Random accidents theory, I mentioned it, and that would be my answer if I accepted evolution. But look at the way Larry worded the question:
He was asking why are there six codons for arginine, not why is arginine represented more than tryptophan on average in life.
So the question sounds a bit bass-ackward to begin with.
So why are there six codons for arginine? Was that a frozen accident?
This is almost like asking why should the codons be:
CGT, CGC, CGA, CGG, AGA, AGG instead of something else.
If this is driven by chance, or at the very least by a mechanism without foresight, then why should arginine have six codons? Is there some biochemical reason it has to be six, and those six in particular? I don’t think so.
stcordova,
Still a dumb answer, Sal, sorry. Particularly in your ‘what I would say’ version. Classic Texas Sharpshooter.
The modern 20 acid code arose from one with a smaller library. The tRNA triplet is not precisely planar, so there is uncertainty, particularly at the 1st and 3rd posiitions – the ‘wobble’ rules. So frequently, at those positions, the base either does not matter at all, or can be either purine (or either pyrimidine). Arginine shows both these. It has 1 4-codon group, where it does not matter what the 3rd base is – any CGx codon will do. And it has one group where either of the purines will do at that position. The latter group may have all coded for Arg once, but Ser was added, with a distinction on pyrimidine, and so 8-fold redundancy became the modern 6.
Look at Trp, however. U-purine-purine is a STOP for 3 of its four possibilities (excepting only UGG – TrP). But even UGG is a STOP in some organisms, or their mitochondria. And even in some organisms that code UGG – Trp, it is a functional STOP when it appears towards the end of an ORF, but a Trp earlier in the frame.
So the evidence is quite strong that UGG was a STOP until fairly recently. You don’t have the same opportunity to subdivide codon groups in the modern code as may have been available previously. And particularly round U-purine-purine, which isn’t a coding group anyway, but a STOP group.
Is that a fact?
And we know this because we have found this alternative code in actual living organisms and the fossil remains of ancient organisms?
And that means there was a smaller library because … ?
Mung,
I anticipated this knee-jerk reaction even as I posted. I figured Frankie but, meh, Mung.
Suppose it was a fact. Suppose it actually was the case that the modern library was generated from subdivision of a smaller one. It would certainly fit the evidence pretty well, and it would be a fact. But apparently it can’t be a fact because we don’t have any organisms with the smaller code. So even if it were a fact, we could simply deny it. And yet, we’d be wrong.
If it satisfies you to stop there – to stop at the point we are all descended from: LUCA – then we simply cannot derive anything from clues we retain – even though there is a substantial body of evidence that the code was historically smaller. Because we don’t have the organisms, or we can’t do one of the other dumbass Creationist notions about How To Do Science such as demonstrate the code evolving.
Because there were only 19 acids, duh.
Although that particular statement was not made in support of the smaller library notion anyway, but part of the broader answer to the question. ‘why 6 plays 1’.
Allan Miller,
What type of cell was LUCA? How close do you think it is to modern yeast?
So when you say there was a smaller library, you didn’t mean a smaller library of codons or tRNA’s, just that one codon coded for something else, other than Trp?
colewd,
As close as it is to a modern human. ie, not very.
Mung,
No. STOP isn’t anything else. When UGG was a STOP, there were 19 acids instead of 20, because there was no Trp.
(Our mitochondria use one of the other STOPs as Trp too, btw. They’ve gone one better, or we’ve gone one worse).
But yes, library of acids, I meant.
I appreciate your comments, but your response doesn’t seem much different than a frozen accident response. Why does Arginine and not Trp get the 6 codon assignment.
The issue is not the lumping of Codons together, per se. You addressed the lumping quite well of some amino acid, but not Arginine vs. Trp in particular. So you say Trp evolved later. Ok, why would Trp evolve later.
Do you think Trp is inessential? It is essential for humans at least.
Trp is listed as an essential amino acid, which I’ve argued against, is a misnomer because maybe every amino acid is essential.
So you think Larry wants to say an “essential” amino acid wasn’t really essential, therefore it evolved later.
Do you know of any organism that builds proteins free of tryptophan?
I mean, Larry is asking for critical thinking. I don’ think this is outrageous thing to ask.
If Larry wants me to say, “tryptophan was not essential then, even though it is now, therefore it evolved later” that’s fine. But I want to know what the data actually say vs. a speculative scenario that the first life didn’t need tryptophan.
This is the only hit I got on tryptophan-free proteins:
https://www.ncbi.nlm.nih.gov/pubmed/18223
I did however find tryptophans role in topoisomerases, like:
http://www.cell.com/structure/fulltext/S0969-2126(03)00214-4
So on what grounds can Larry say Tryptophan is non-essential?
Bottom line, I think the answer Larry is fishing for is a rush to judgement. But your response at least gives me an idea of what it would take to give him the answer he wants.
Now, I should point out something different in his philosophy of teaching biochem vs. other biochem instructors:
Oh wait a minute, even by Larry’s own admission, what he said also implies the teaching of evolutionary concepts inhibits the preparation of students to medical school!
When critical thinking examples are placed before students at the biochem classes hosted at the NIH, the critical thinking usual goes over medically relevant biochemical experiments. I really don’t remember a single example on an exam question that asked about evolution. This class is oriented to prepare students for the MCAT (medical school entrance exam). Only one MCAT review question brought up in class dealt with an evolutionary question about symbiosis or something. But we weren’t tested on it. There’s a lot of biochemistry to learn regarding the operation of biochemistry in the present day. Those seem more operationally and medically significant than speculations about what may have happened in the past.
I think question like this are more important:
Speaking of which…
stcordova,
Because 6 is the residue of a larger codon group previously taken by arginine, which is fundamentally due to only the 2nd base being recognised with full 4-way specificity – other positions are 2-fold or 4-fold degenerate, with either no distinction or distinction merely between purine and pyrimidine.
As acids are added to a library, the number of codons taken by one of the ‘ancestral’ acids must go down. Trp, meanwhile, isn’t taking a coding codon at all, but reassigning a STOP. This is not a ‘frozen accident’ view. Or, at best, gradual crystallisation, rather than instant deep-freeze. The historic process was dynamic, and shaped by its own consequences. As assignments became more subdivided, and proteins more widely used, plasticity reduced, although the code is not absolutely fixed today. 9 of the 64 positions varies, all of which are a STOP somewhere.
Because it did not evolve first … it had no role till it existed.
Trp is present in all branches of life, so the assignment must be ancient on that scale. Nonetheless, the fact that UGG is a STOP in some organisms – including at least two proteins in humans when it occurs near the transcript terminators, but not elsewhere, is indicative that Trp is a comparative latecomer, and arose by reassignment of a STOP. Its neighbour STOP, UGA, is Trp in our mitochondria. There is therefore some residual ‘uncertainty’ about what UGA/UGG actually are – even within the same organism. Even we humans use both UGA and UGG as both Trp and STOP. I suspect this kind of lability was common in the more ancient codes, and represented a typical transitional picture as acids were added.
stcordova,
God no. Essential amino acids are those that are required in the diet – ie the organism has no synthesis pathways. It is not a judgement on how imprortant the acid is in the organism’s proteins.
Right. It’s essential for all life we know of now, because it’s part of pretty much all proteins. But are versions of those proteins without Trp possible? Yes.
So it’s conditionally essential, as a product of historical development and natural selection. Not due to some fundamental constraint operating on any and all possible protein-dependent life.
The fact that having Trp among the amino acid alphabet of life is selectively favorable, does not mean it is fundamentally required. Proteins with Trp in them could be altered if Trp was missing, such that they still worked.
Why would Trp evolve later? It’s a strange sort of question, “why?”.
I think a better question is why do biologists think Trp evolved later? Because of data that we want to explain. Patterns in life, between different species in different domains, and for individual molecules involved in the translation system and the genetic code. Patterns that only evolution can make sense of.
Starting from the bottom up. What would our knowledge of physics and chemistry predict, if the genetic code started in an environment where the first amino acids were nonbiologically synthesized by essentially abiotic chemistry?
Evidence from the thermodynamic basis of amino acid synthesis:
A thermodynamic basis for prebiotic amino acid synthesis and the nature of the first genetic code.
Higgs PG1, Pudritz RE.
My bolds. Read the paper for details.
Okay. What can we infer about early life when we look at the patterns of distribution of amino acid usage in extant life?
Evidence from comparative genetics of components of the translation system and the genetic code:
Evolution of amino acid frequencies in proteins over deep time: inferred order of introduction of amino acids into the genetic code.
Brooks DJ1, Fresco JR, Lesk AM, Singh M.
More of this:
Increased frequency of cysteine, tyrosine, and phenylalanine residues since the last universal ancestor.
Brooks DJ1, Fresco JR.
Even more:
Signature of a primitive genetic code in ancient protein lineages.
Fournier GP1, Gogarten JP.
Whatever you may think of the speculations that follow the empirical results of their investigations, the fact is biochemists consistently reconstruct a similar picture for the evolution of the genetic code and the order of inclusion of amino acids over the history of life.
More directly relevant evidence for the “late” addition of Trp, compared to other amino acids:
Ancestral Reconstruction of a Pre-LUCA Aminoacyl-tRNA Synthetase Ancestor Supports the Late Addition of Trp to the Genetic Code.
Fournier GP1, Alm EJ.
So all of this evidence is actually internally consistent. Comparative genetics recapitulates an early genetic code that looks like the sort of genetic code one would predict to originate in an environment where the first amino acids to be used are those most frequently produced by spontaneous chemistry.
More detailed looks at the patterns of similarities in the sequences of key molecular components of the translation system, such as aminoacyl-tRNA-synthetases, also show that primordial codes lacked Trp and even that they evolved from the Tyr aaRS enzyme by duplication. Which is ALSO consistent with the two other lines of evidence.
What remarkable coincidence. That your designer would just so happen to distribute the usage of amino acids in the folds of extant proteins such that, when compared under the assumption of sequential stochastic change over geological time, it looks like it’s coverging on the same distribution of amino acids one would predict (and we have indeed observed) to be produced by spontaneous chemistry.
Even more remarkably coincidental that comparative genetics of translation system enzymes such as aaRS, mirrors these findings.
Oh gee, maybe evolution really happened. Nope. A wizard did it. Just ignore the patterns we observed. They’re artifacts of sheer luck. Or maybe Satan put them there.
Sure, all amino acids, in so far as they are used for essential proteins, are essential. Were they to disappear, those proteins would be biosynthesized incorrectly or not at all, and chances are the organism would die.
But are they essential as a byproduct of historical development and selection, or are they essential due to some fundamental constraint operating on all protein-based life?
Yes. It was not essential before it evolved. It was selectively favorable, as it’s inclusion offered expanded structural and biochemical properties to proteins and enzymes.
Yes, now. It’s essential now, because it’s part of almost all proteins, and where it is included, it’s role has become critical for correct function of those proteins.
But there is evidence that functional versions of those proteins existed before Trp was included. From ancestral sequence reconstruction and comparative genetics, as seen in the references above, and from broader simulation studies that attempts to estimate whether reduced amino acid alphabets could still encode functional versions of extant proteins:
Are proposed early genetic codes capable of encoding viable proteins?
Angyán AF1, Ortutay C, Gáspári Z.
When Trp was included, the amino acid sequences of those proteins changed around it too, besides the mere inclusion of Trp, such that if you were to remove that Trp again, the rest of the protein would adopt a different conformation and fail to function properly.
Trp, while initially either beneficial or neutral (or perhaps even slightly deleterious), also opened up for additional epistatic mutations that works in synergistic fashion together with the Trp inclusion. Obviously if we remove it now, all those compensatory changes that work in conjunction with Trp, now are missing that critical component, and so will probably fail.
See how that works?
Then start thinking critically, with a view that also considers historical change, rather than these absurdly rigid conclusion-first “must-be-as-they-are-now” Irreducible Complexity-strawmen.
One way of thinking critically is to consider all options thoroughly. And not ignore a lot of evidence. Or brainlessly dismiss it as “what the designer wanted because he’s just sort of a creative guy who likes to play pranks”.
It’s not just a speculative scenario. It’s what the evidence actually shows.
Rumraket,
It’s not necessarily the case that this indicates extracellular, nonenzymatic origins though. One would expect enzyme-catalysed reactions to follow the most thermodynamically favourable routes first, which happen to be those that can occur non-enzymatically.