Note: the second figure has been replaced with the correct one, twice. A xylulose bond was in the wrong direction. This is hard.

There are a couple of other origin of life issues that I haven’t focused on yet. One that I was hoping would reveal itself is the issue of “chirality”, or the side of a molecule a bond or atom is on relative to the rest of the molecule in 3D. The strict definition includes things with identical chemical formulas having non-superimposable structures.
I don’t tend to draw in 3D to simplify things. I also don’t include hydrogen to simplify things.

I meant to address this in a previous post where I posted this figure of thiamine and parts of the pentose phosphate pathway. It’s why there is a single hydroxal on xylulose-5P drawn in 3D as if it’s coming at you out of the page. I’ll get to that at the end.

I’ve drawn ribose and xylulose in 3D. Both looking down the length of the molecule and from the side. Carbon actually binds 4 things and is tetrahedral like a pyrimid. So I put the hydrogens back into the upper structures and used conventional dashed and filled wedges to represent bonds going into and out of the plane of the page respectively.

Each of those hydroxals could be where the hydrogen is on the carbon instead. If you flipped the hydrogen and hydroxyl on ribose you can see how the formula would be the same but the structures would not be superimposeable. Things on different sides are designated with R/S or D/L distinctions that refer to single atoms on the structure. D-ribose refers to the stereochemistry around the atom farthest from the aldehyde group in the form of ribose used by life.

Amino acids are all L- relative to the side chains aside from glycine which has no atoms with stereochemistry.

So why is life one way and not the other when it comes to these bond directions? I don’t know but I noticed that the only sugar with a bond in the other conformation is xylulose-5P so I drew that one bond with 3D on the thiamine figure. The rest are in the other confirmation. And xylulose is the donor for the pentose phosphate pathway 2C molecules. This isn’t a solution to the chirality problem but it is a clue.

This post is going to look at something I found from the results of 2 studies looking at the ribosome, the molecular machine that translates the genetic code into a string of amino acids that fold into the 20,000+ proteins that build and make us.

The first paper Evolution of the ribosome at atomic resolution peels the large subunit ribosome apart stem-loop by stem loop. They have a second paper with the small subunit which I took some figures from. A stem loop is a loop shaped structure where you have a base paired nucleotide “stem” and above that the rest of the structure forms a “loop”, often with more stem parts. These are how ribosomes tend to evolve. Sequence changes have more of a negative effect than insertion of something that adds new functions.

In the top portion of the figure from their second paper they compare a similar region of ribosomal RNA (rRNA) from different species where you can see how new loops are added.

They went through the ribosome and figured out what stem loops were added where and peeled additions away down to a first rRNA “hairpin”, named “AES1” for “ancestral expansion segment 1” in capital letters for the large subunit and lower case letters for the small subunit. I’m interested in the large subunit because it older. More recent segments are AES2…AES3…

This second figure shows the base pairing in the large subunit. The top is numbered by their expansion segments and the bottom is colored by 6 phases of evolution they identify. The part I’m interested in is #1 in the upper right by the “PTC” in the lower right.

AES1 is associated with the Peptidyl Transferase Center (PTC). The region that does the actual connection between one amino acid and another in creating a new protein.

The second paper The ribosome as a missing link in the evolution of life looked at the sequence of rRNA and did a search of other genes to look for similarities and found some very interesting things. I should emphasize that the rRNA is not transcribed into products as far as is known. But that may not have always been the case.

They find the transfer RNAs, tRNAs, that escort the amino acids to the ribosome. They find lots of parts of ribosome and RNA related proteins. They find ribosomal proteins, polymerases, and more.

From these data sets I identified the sequences associated with the oldest fragment of the large subunit, AES1, and went and looked at what was in it.

I found parts of 5 things:
1) GshA Glutamate–cysteine ligase
2) Protease 4
3) RecF a DNA replication and repair protein
4) PqqL a probable zinc protease
5) RplB/Ribosomal large subunit protein 2

Things that attach and cut amino acids, proteases. Interesting. A protein that binds single stranded DNA during repair and replication, RecF. And one of the first ribosomal proteins to bind the large subunit rRNA, one that accesses the PTC during translation, RplB. Very interesting.

I’m not really functional for human behavior related posting, but thinking about the molecules is a hobby and I’ve been able to improve on the drawing I did in my previous post. I actually might have enough origin of life material for 4 or 5 posts. This post will be limited to the overall patterns in the drawing and the most interesting thing I’ve found in the subdomains so far. All of these posts will be like collecting puzzle pieces to the origin of life.

After more time with my drawing I’ve decided that it’s better described as a metabolic alignment of everything related to DNA that I can fit into a canvas. The file is too large for me to post on WordPress so I linked a Google documents version again. To properly figure out biological origins the sequences of genes and proteins aren’t enough. The very metabolism of these things should be considered. I’ve been careful about the structure of the alignment. Even now I’m thinking about how it could be improved with more room or simpler representation. There’s only so much I can do to compact the information down.
It’s a complex set of interconnected notes useful to anyone interested in the origin of life. This one is even cleaned up and error checked.

Cells are relationships between nucleic acids and proteins. Ribosomes and a genome. They make everything between them with the help of some atoms other than CHONPS. That is complex, but not endless. Ribose, 5 bases (A G U C dT), and 20 amino acids.

There is a legend in the top left of the linked drawing. It shows that each molecule is positioned with the protein(s) that use it. So the molecule is the product of something tangential to it shown by arrows, and the MAIN product of the reaction carried out by the protein(s) is also tangential.
Positioned right to above the molecule are other reactants and catalysts, and positioned left to below are products of the reaction.
The name of the protein(s) is given with the length in amino acids. Below that is every identified subdomain in the protein in order, and the protein domain superfamilies they belong to according to the Evolutionary Classification Of protein Domains database (ECOD).
Occasionally the molecule is below a protein when it’s a product of something already present on the figure nearby, like 10- formyl tetrahydrofolate (thought to be a storage form of formyl groups).

There is also a list of molecules that make an appearance in the top right. From 1 to 5 carbons and larger molecules.

In addition to the Purines (A G) and Pyrimidines (U C dT) are:
The amino acids Histidine, Methionine, Phenylalanine, Tyrosine, and Tryptophan.
The cofactors Thiamine (vitamin B1), Flavin (vitamin B2), Coenzyme-A (vitamin B5), the vitamin B6 group (pyridoxal…), Niacin, Folate, S-Adenosyl-Methionine and Molybdenum Cofactor.
These are boxed in blue for the amino acid product or first usable form of cofactor. Molecules that follow this box are different forms of the cofactor used by proteins made from the basic form (folate, molybdenum cofactor, vitamin B6, flavin too but I haven’t included FAD yet).

A cofactor, or coenzyme is a molecule that participates in what the protein is doing. The protein is just the polypeptide part. You can think of them as tools that often have to be reloaded when they dispense things. ATP itself is a cofactor as “energy currency”. The amino acid glutamate is a cofactor for dispensing ammonia. Cofactors also act as platforms to build things (coenzyme-A), or move things to other things (Thiamine), or move electrons around with charge so chemistry can happen (vitamin B6).

Overall Patterns

The whole thing is roughly centered on the purine (A G) pathway going from left to right and bent downward halfway through. Ribose-5P sits in the upper left corner in a small red box. The purine pathway is boxed in red as well. The products are marked with a large black A and G.

The pyrimidines are lined up and go down where the purines bend down. This is deliberate because parts of both pathways involving the amino acid aspartate and bicarbonate (HCO3) are close to one another. Large black letters mark the products similarity to the purines. From there continuing to the right I have niacin, methionine (and SAM), and coenzyme-A allowing a similar grouping of aspartate in those pathways.

Thiamine is above the purines and I’ve lined its glycine up with the one in the purine pathway.

Under ribose-5P and traveling downward are the vitamin B6 group and “aromatics” which are tyrosine, phenylalanine, tryptophan, and part of folate called PABA. All from the same pathway. The B6 group uses ribose-5P and the aromatics use erythrose-4P so they made sense together and near ribose. 5C sugar, 4C sugar…

Histidine, folate, flavin, and molybdenum cofactor branch off from the ends of the purine pathway where A and G separate. They are made from A and G, where many of the previous molecules have A attached as part of the structure.
This whole section has the feelings of “partly deconstructed purines” to it, and deconstructed ribose in the case of tryptophan.

On the whole there is a feeling of there being an aspartate accumulation after early purine evolution (if the pathways can be read like that). Maybe aspartate was the first nitrogen delivery molecule. That it’s a part of the purine pathway, used for so many cofactors and amino acids, and delivers purine nitrogen is significant.

Purines and Pyrimidines, General Patterns.

To simplify discussion of some of this I drew a separate purine and pyrimidine pathway that just focuses of the overall patterns.

The purine pathway that makes Adenosine monophosphate and Guanosine monophosphate is unique in that it is constructed from smaller parts relative to all of the other pathways presented, outside of the ribose-5P. The biggest thing is glycine, the smallest amino acid, in the formation of the smaller 5-membered ring with ammonia and formate.

Aspartate, the amino acid used in making pyrimidines, temporarily joins in making the second ring. It attaches by it’s nitrogen and leaves as fumarate (tricarboxylic acid cycle). Bicarbonate (or carbon dioxide in later organisms) is the only other thing in the pathway left to mention. And the way it’s attached to the former glycine makes a 3-carbon segment. It’s a 2C-3C transition. Maybe it means something. Carbon fixation would be different things at different metabolic levels.

The pyrimidines have the opposite relationship to ribose-P as the purines. The ring is made first and then it is mounted on the ribose via PRPP, the form of ribose used to make nucleotides (and niacin, tryptophan, folate…). A bicarbonate and aspartate are combined and made into a 6-membered ring like the second ring of the purines. Getting aspartate and bicarbonate together in the figure makes sense when it comes to positioning the pathways together.

Both pathways make an intermediate that isn’t used for anything else. Inosine monophosphate and orotidine monophosphate. After that it’s smaller changes to get each of the final nucleotides.

The pyrimidines also lose parts of structure. Niacin removes 2 hydrogens and their electrons making a double bond. After orotate binds ribose it loses a carbon dioxide (decarboxylation). And the only place DeoxyriboNucleic Acid shows up is deoxythimidine, a loss of a hydroxal. That’s done with purines too but I didn’t need to show deoxyribonucleic acid until dT.

Maybe there’s a progression here with 5 ring ancestors and a 6 ring newcomer. Early base pairing between them. I certainly think accumulation of aspartate is a theme in both the evolution of pyrimidines and much more. In fact I think modern genomes and ribosomes are descended from something like the 5-membered thiazole in thiamine on a ribose maybe. With chemistry and base pairing between strands.

The purine pathway splits to thiamine biosynthesis at AIR, but the molecule is turned into the 6-membered ring of HMP. Not the 5-membered ring that moves carbon in making ribose (pentose phosphate pathway), the part that assists in the chemistry (more on that at the end)

Purines

I think there is a level where one can tentatively delete whole parts of proteins when thinking about precellular life in the vent. Formate, methane, bicarbonate, acetate, ammonia, phosphate were just tentatively available. There is sufficient literature support for these molecules in the vent from my point of view. As well as acetate, pyruvate, and fatty acids that make membranes.

Extreme accumulation of ammonia on electroreduced mackinawite: An abiotic ammonia storage mechanism in early ocean hydrothermal systems

Generation of long-chain fatty acids by hydrogen-driven bicarbonate reduction in ancient alkaline hydrothermal vents

Bio-inspired CO2 conversion by iron sulfide catalysts under sustainable conditions

Phosphate availability and implications for life on ocean worlds

I’ll only mention the most interesting thing I have found in the protein subdomains in this post.

Focusing on the purine pathway there is another maybe link to the origin of life. 3 polymers are important in life and origins: polynucleotides (DNA RNA), polypeptides (proteins), and fatty acids (~16-20 carbons, membranes and cofactors like biotin). Not only are nucleotides being made but step 2 of the purine pathway has a product, phospho-ribosyl-glycin-amide, that looks like a peptide (protein) bond on ribose between the glycine and the ribose-amide.

Maybe it doesn’t mean anything but get enough interesting things together and there is more room for thought.

The protein that does this step, PurD, is an example of something that I can cut a lot of things off of, just for fun. PurD is a member of the ATPgrasp family of proteins. These proteins bind an ATP, and pop a single phosphate off making an ADP.

When a protein uses ATP as “energy currency” in this way it either participates in a chemical reaction directly or it drives physical movement of a protein to do something else including chemistry. The metaphor is about doing work. Here the phosphate directly participates in attaching glycine to the nitrogen added in step 1 with a glycine-P intermediate.
The ATP-Grasp Enzymes

Structural biology of the purine biosynthetic pathway

Here is where the chopping out can happen. In the vent there is phosphate. The ATPgrasp family is essentially a bunch of phosphate dispensers and just for fun can be deleted in terms of what is more or less interesting here. That being said phosphate control seems to have evolved first/early
Structural Phylogenomics Reveals Gradual Evolutionary Replacement of Abiotic Chemistries by Protein Enzymes in Purine Metabolism

And the ATPgrasp family is related to the protein that puts aspartate on CAIR in the  purine pathway which is interesting.

That’s most of the protein deleted, except for the C2 domain. It’s an interesting little piece and it’s relatives are involved in some very origins related chemistry. At the Evolutionary Classification of Protein Domains database this domain is in the “Alpha helix + beta sheet complex topology” bin. And in there it’s in the “alpha/beta-Hammerhead Barrel-sandwich hybrid” X, H and T (homology, topology) groups.

That whole T group is filled with interesting stuff but the PurD C-terminal fragment is in the “CO dehydrogenase molybdoprotein N-domain-like” F or family group. It’s relatives include not only the above CODH MO-N fragment (1C+1C) but is also in biotin carboxylase (1C manipulation), acetyl-CoA carboxylase (1C+2C, on the drawing), and pyruvate carboxylase (1C+3C).

No where else do I see a numerical progression like that. Where did aspartate come from for pyrimidines? Today cells can use pyruvate carboxylase to make oxaloacetate in initiating gluconeogenesis (glucose synthesis), which is also made into aspartate. Interesting.

This “CODH MO-N fragment” is also in 3 other purine biosynthesis genes, PurT, PurK, and PurP. They involve formate, and bicarbonate. Carboxylations use bicarbonate. The fragment is also in L Amino acid Ligase (LAL). And it is present in a few proteins without the ATPgrasp part: xanthine dehydrogenase chain B, Carbon monoxide dehydrogenase large chain (so  2 parts of CODH), aldehyde oxioreductase, quinoline 2-oxidoreductase large subunit, and 4-hydroxybenzoyl-coa reductase large subunit. I don’t know what to think about the things in this paragraph yet but I mention them for completeness.

The last thought on this fragment is that the general shape of the carboxy HO-C=O, or even the carbonyl C=O itself is maybe what it is about. I need to look at protein structures.

Ribose

I’ll finish with some thoughts on ribose. I’ve been hoping the origin of ribose comes out of this. There are different variables to consider in the abstract. The polynucleotides are the most complex part of this. Only counting genomes ribose:
1) Has 5 carbons with hydroxals on 4 and an aldehyde on one end. Each oriented the same (chirality).
2) Polymerizes using phosphate on the carbon on the end opposite the aldehyde (#5) and 2 carbons over (#3). So a 3-carbon segment for the backbone.
3) Provides a site for nitrogenous base binding at the aldehyde carbon (#1). This also provides a site for base pairing between strands.

Each of those variables is modifiable hypothetically.

Maybe there were things with erythrose-4P or shorter in the backbone of the polymer. This still allows for base pairing. With glyceraldehyde-3P maybe you still get the same but no ring.

But it’s the predictability of the ring that evolution can respond to. There is a huge diversity in things that bind ribose or things with it. Erythrose is only used in a few other places outside of the pentose phosphate pathway and the pathway that makes part of folate, tryptophan, phenylalanine, and tyrosine. And a 2-carbon segment in the backbone might be too close for 2 phosphates, steric hindrance (physically interfering).

If you get larger than ribose then you worsen the problem of self splicing, poly-RNAs of a certain size looping out and removing part of themselves and sealing the break. Removal of the #2 carbon reactive hydroxal that is removed in Deoxy-ribonucleotide genomes is bad enough, 2 would allow for more chemical possibilities than the relative stability of 1.

Getting outside of genomes carbons #2 and #3 bind amino acids in translation with class 1 and 2 aminoacyltransferases. Maybe there’s evidence of an erythrose backbone and only carbon #2 binding amino acids in the past there, but probably not.
Carbon #3 also binds phosphate in coenzyme-A and niacin in its anabolic mode (the NAD/NADP difference).

Carbon #1 binds lots of cofactors, mostly through at least 1 phosphate as the drawing shows. It also binds lots of other things for transport like sugars, membrane components, and more. Carbon #1 also binds all amino acids during the process of aminoacyl transfer in creating transfer RNA loaded with an amino acid, again on one phosphate, aminoacyl-AMP.

These carbons are also used in making signalling versions of nucleotides like cyclic AMP and cyclic GMP. The signalling functions of nucleotides is an area I’ve yet to get into in depth and integrate into this.

Finally the metabolism of ribose on the figure may provide clues to its origin. In the cofactor pathways ribose is often partially dismantled with pieces leaving, such that 4 or fewer carbons from ribose remain in the final molecule. At the least it makes me think about the assembly of ribose and its own abiotic concentration.

3C+2C?
4C+1C?
6C-1C?
3C+3C with loss of OCO?

I think the first and maybe last follows the most likely routes. 3 comes after 2 and if 2 is already around… It’s maybe thiamine related.

Common ancestry between the purine and thiamine pathways is possible and likely given the use of AIR in making HMP. Attaching glyceraldehyde and glycoaldehyde could be a route. Now how would acetate and pyruvate become sugars? Something between oxaloacetate, gluconeogenesis and the pentose phosphate pathway maybe.

Update

I’m much better in terms of hypervigilance. But it’s still useful to keep my number of social spaces to a minimum while I think about social variables around me. “Social firmware update”? It makes sense that groups would complicate that. “Gender-Null” still makes sense. It’s easy to just be “like everyone” when the group is more sensitive to the words than me. I make choices with the words. Relative to tourette syndrome maybe it’s an “intense words” thing. I make choices with lots of words that other people feel intensely about. This is not to say that tourette syndrome and non-binary or gender-null are connected, rather these parts might have connections for me.

I can’t say this is me going back to blogging on a regular basis either. This is more like I have a creative project connected to a lot of feelings about what I wish I was doing professionally, origin of life research. Obsessing over brain science is more of a defence mechanism, this is an older obsession and it’s not only interesting but I may get some benefits out of it. Lots of feelings here.

I have spent a lot of time drawing metabolic pathways until I can do it from memory as a way of internalizing them. More body parts and sensations involved enhances memory. Drawing anatomy is helpful too. And I’ve had a lot of time to think about the patterns. I’ve come back to one project over and over and I recently got a tablet with a good screen for drawing and transferred the latest version of a group of pathways to Sketchbook. I’ve also started using Kingdraw for molecular structures.

BUT, I can’t just post this drawing by itself. If you have a strong background in molecular biology you can skip to the end (check out the transcription and translation diagram though, I integrated aaRS class information in with the genetic code) but for everyone else I need some figures to make this somewhat more meaningful. An attempt to go from public perception to hardcore molecular biology.

This is for fun. I’m playing with the ideas and concepts. So there is a lot of me imagining things in here but I try to be clear about what is data and what is me speculating. Other views are welcome, including data that suggests I’m wrong, or people who have made the same observations that I missed. This is a work in progress, but keep in mind that this is about fun.

From public perception to molecular biology.

The perception about A G U C T nucleic acids are usually understood by their relationship with amino acids through the genetic code and the making of “proteins”. Equating the metaphorical “hard drive” with its products hides the full range of relationships that must be taken into account, even pinning things relative to DNA sequence or protein sequence.

The letters pop up all over culture, but usually not the “U”. Here’s what that looks like in detail, the drawing includes the pathways that make these molecules. And metabolically related molecules.

Briefly, the Deoxy-Ribo-Nucleic acids are “duplex chains” of -ribose-phosphate-ribose-phosphate- with Adenine, Guanine (purines), Cytosine, or Thymidine (pyrimidines) attached to the Ribose by the 1′ Carbon (read as “one prime carbon” ). The structure of the “nitrogenous bases” is such that attractions (hydrogen bonds) between molecules allow A:T and G:C pairing between the strands.

Triplets in those chains (with 3 reading frames on each strand) are a basis of the “genetic code” used to synthesize the proteins in a cell. A “protein” is a chain of amino acids.

Below is the simplest amino acid, Glycine, and water in even more detail so I can show some more molecular features that can be referenced in the future. The previous figure omitted them and following ones will as well to simplify things.

The previous base-pairing diagram omitted parts of molecules worth mentioning that aren’t often represented.

• Ionic charges. Many of these molecules are actually ions in water, amino acids lose a proton (hydrogen nuclei) on one end, and gain one on the other (center versus right). This comes down to some atoms having more “electronegativity” than others (nuclei attract electrons more strongly) Most of the time I don’t do this to save effort.
• “lone pairs”. Oxygen and nitrogen atoms have electrons in “non-bonding orbitals” (the places electrons go). These regions are more negative while not being full ionic charges, called “polar” . That’s why nitrogen atoms can either attract or repel one another in the base pairing. If a hydrogen is sticking out from one base and a lone pair from another they attract.
• Water also has lone pairs, it’s actually a pyramid shaped, highly polar molecule. There is no “hydrophobic”, water is attracted to itself and crowds non-polar molecules away as it is attracted to itself. I also mostly omit lone pairs to save effort.

Now for all of the amino acids your body, and all cells, use to make proteins.

Cells use these 20 amino acids to chain together “poly-peptides” (the bonds are called peptide bonds) that do biochemistry or make structures. Essentially they are glycine + something at a specific carbon. (There’s a layer called chirality I’m not getting into yet, the hydrogens on that carbon aren’t the same chemically and biology uses one here).

This is my own take on how to organize them. There are 2 organizing principles; metabolic relationships, and atoms in the side chain.

The untitled block on the left roughly acts as precursors for ones to the right. There’s a system that can generate serine from glycine and back as the cell needs. Serine itself can be used to make cysteine. Larger amino acids can be broken down into smaller ones too.

The “aromatic amino acids” (Phe, Tyr, Trp, named for the benzine ring) are complicated because they are made from 3 carbon and 4 carbon molecules. So I put them on a different level.

Tyrosine and histidine are close because they both use ribose in their biosynthesis.

Making proteins from DNA.

This is a simple protein made with the previous “proteogenic amino acids” (cells use these). The next figure will explain how, and why methionine is first.

This is how cells make proteins with DNA sequences.

This figure starts on the top left with the DNA genome, so named because it contains the “genes” expressed into proteins (now more complicated due to RNA genes). Some cells have “linear” chromosomes of 100’s of millions of base pairs (genome segments), and bacteria tend to have small genomes of a few million.

The DNA is separated into it’s 2 strands and one strand acts as a template for copying a part or all of the genome. That copy of a part is made from RNA in a process called Transcription. The copy is called an “mRNA” or “messenger RNA”. Many proteins are involved.

The mRNA is escorted to the smaller half of a massive 2 subunit complex called the Ribosome where the nucleic acid sequence is transformed into a poly-peptide sequence. The small subunit (SSU) contains an RNA called rRNA or “ribosomal RNA” and 20+ proteins in bacteria.

After the mRNA docks with the SSU a large subunit (LSU) made from 2 rRNAs and 30+ proteins in bacteria docks with the small subunit.

Small (50-70 nucleotides, nts) RNAs called transfer RNAs (tRNA) bring in amino acids one at a time and a 3 nucleotide sequence in the mRNA called a “codon” determines what amino acid is placed through binding to an “anticodon” on the tRNA. (In the bottom-left I show an intermediate in the aminoacylation of tRNA, an aminoacyl-AMP intermediate.)

Both protein and RNA are involved in aminoacylation.

A 3 codon system gives 64 possibilities and the way those are arranged is the generic code. 3 of these are reserved for STOP: UAA, UAG, and UGA. Methionine doubles as START with AUG.

There are 2 classes of tRNA and systems of attachment of amino acids to tRNA. The aminoacyltRNA transferase systems. Class 1 involves attachment of amino acids to the 2′ hydroxal of ribose, class 2 involves attachment of amino acids to the 3′ hydroxal of ribose. On the figure I have listed the classes and subclasses under the relevant hydroxals and listed their codons next to them.

The ribosome subunits hold the mRNA, and the tRNAs in place and one amino acid is added at a time while empty tRNAs leave. Eventually a STOP is reached and a new poly-peptide/protein is released from the exit tunnel of the large subunit.

These proteins are then often modified in many ways and transported to many places to do their structural or catalytic jobs.

The genetic code relationship plus ribose metabolism.

That is not ONLY how I see these things. I also see the individual biochemical reactions that cells use to make nucleic acids. Starting with RNA. (Anabolism=construction, catabolism=breaking down and I will need to look at catabolism at some point).

DNA as a physical substrate for molecular biology, our “hard drive” is based in RNA metabolism. And so the metabolism of RNA, not deoxy-ribose is context to understand these relationships. (Deoxy-nucleotides are definitely part of the story though.)

Ribose centered metabolism.

Note that this is at lower resolution but still ok for display. A full resolution version can be found HERE.

This is a Ribose centered metabolic diagram. A tool for thinking about how metabolism can tell us where nucleic acids and proteins came from. They have metabolic relationships beyond the DNA>RNA:>Protein one. These are parts of that relationship.

All of the hydrogens are implied to save space and work. Each protein is named with type instead of written so they stand out. Each protein is positioned with the molecules they interact with, and are products of the previous protein(s).

This is a prokaryote centered metabolic diagram. It’s been difficult to get interested in us bacterial-archal fusions (eukaryotes) here. The blending complicates the picture.

Beneath each protein is the length in amino acids, usually from E.coli strain K12 unless E.coli was the exception relative to cells in general. I’ll get around to citing everything eventually but I can get specific things if someone wants something. I’ll put some sources of information at the end, and here and there in the text.

Along with the length I list each known subdomain within the protein and the protein domain families and superfamilies to which the domains belong. These parts of proteins are related to one another and their relationships are part of the puzzle. I go over an example with PurF in the resources section. These bits of related protein often have themes to what they do, and can potentially lead to primordial subdomains.

Black arrows point in the direction of biosynthesis.

This is a very unfinished diagram. Once I did The pathways that produce the bases in nucleic acids I kept adding Ribose related pathways and I’m not done. This is maybe the 20th iteration and I keep adding elements and reorganizing.

My intention is to upload and comment on new versions, as well as adding new categories of information as big as protein subdomains (below). There are likely errors here (PurF is a GATase class 2!!! I keep putting class 1, I used PutF as an example in the references with correct info and this will be my first correction,) and after and once this is up I’ll do another error sweep before doing more. There is fading and smudging from copying and pasting. And I’m still making decisions on how I’m going to represent things so there may be inconsistent bits.

The following pathways use ribose in the form of Phospho-Ribosyl-PyroPhosphate, PRPP.

• The Purines: produced as Adenosine-MonoPhosphate (AMP), and Guanosine-MonoPhosphate (GMP). (Starts center left with PurA, runs right and down, and forks left into AMP and GMP)
• The Pyrimidines: produced as Uridine-MonoPhosphate (UMP), Cyotosine-MonoPhosphate (CMP), and deoxy-Thymidine-MonoPhosphate (dTMP) (Starts at the bottom-left, continues to the middle, and forks into CMP and dTMP after UMP)
• Amino acids: Tyrosine (starts top-left, goes down, turns right to the center, forks right into Trp, and forks up into Phe and Tyr), and Histidine (starts top-left, moves right)
• Cofactors: Thiamine (Vitamin B1, starts upper right under histidine, pathway moves right), Nicotinamide-Adenine-Dinucleotide-Phosphate (niacin, starts lower-middle-left and moves right), Cobalamin (Vitamin B12, starts to the right of NADP, this only covers the part of B12 derived from AIR),and Tetra-Hydro-Folate (to be added).

If someone is wondering why I haven’t added the cofactor that donates the formate for Purine biosynthesis to the diagram, that is an example of going too far with treating things like dispensers of things available in earlier environments. Some organisms use formyl-phosphate. But it still needs adding. Ultimately I’m betting THF, and things like glutamine (the NH3 donor, mostly) are providing things that were environmentally available. THF is a remodeled GMP (like how histidine is a remodeled AMP?) A GMP with an intermediate from the Phe/Tyr/Trp pathway (PABA) added.

Purines and Pyrimidines

The Purine pathway produces A and G. The Pyrimidine pathway produces U, C, and T. These 2 pathways interact with Ribose in opposite fashion. A and G are built onto Ribose bit by bit out of small things and rings are closed. Pyrimidines are made by building a ring and putting them on Ribose. PRPP is also used with whole nitrogenous bases that are already finished.

It might be useful to look at the pathway like this.

Purines: PRPP + NH3 + Glycine + CH2O + NH3 + CHO3 + Aspartate – Fumerate + CH2O = IMP (pathway fork).

That aspartate-fumerate is effectively a 2-step, or indirect amination (ammonia addition) that releases a TCA cycle intermediate.

IMP + Aspartate – Fumerate = AMP

And there that weird amination again. It happens in arginine production too.

I have ideas of different places in time where aspartate and AMP accumulation occured. Maybe glycine accumulation earlier too. How to define the “start” of things?

IMP + H2O + NH3 = GMP.

Pyrimidines: CHO3 + Aspartate – H2 + PRPP – CO2 = UMP

Maybe there was aspartate accumulation with more than one use. A transition from a 5 to a 6 ring polymer (Purine intermediate AIR) leading to Pyrimidines and other things? A step is shared with arginine biosynthesis (CHO3, bicarbonate use through an intermediate called carbamoyl-phosphate).

UMP + NH3 = CMP

UMP + PO4 – O + PO4 – 2 PO4 + CH4 = dTMP

Thymidine stands apart from the other nucleotides in that it is made from Uridine-DiPhosphate (UDP) that is dehydroxylated before being methylated. Since I’m a bit RNA focused I haven’t pursued Thymidine much.

Amino Acids: Histidine and Tryptophan

In histidine biosynthesis a ribose from PRPP is connected to a nitrogen on ATP. The same nitrogen provided by aspartate. Then the ribose leaves with a C-N, and the rest of the ATP is a late intermediate of Purine biosynthesis. Adding an NH3 and some processing gives histidine.

A molecule that is a 4-carbon clone of Ribose-5-phosphate, Erythrose-4-phosphate, is combined with a 3-carbon glycolysis intermediate, Phospho-Enol-Pyrivate, to make a 7-carbon molecule that is processed into a ring before being attached to ribose via an added nitrogen. After that the resulting molecule loses carbons 1-3 of ribose as the glycolysis intermediate Glyceraldehyde-3-Phosphate, a molecule like a 3-carbon Erythrose-3-phosphate (or ribose-5-phosphate) (histidine takes the ones ribose loses here…). That G3P is replaced with a serine to make tryptophan.

Cofactors: Thiamine, NAD, and THF

A cofactor is like an “attached functional module” for proteins. Like different heads on a power tool.

There’s Thiamin (VB1), a carbon group extractor/dispenser. Interestingly AIR is made into the part of Thiamine that isn’t grabbing carbon chains. But it’s rearranged into HMP in an interesting set of reactions where the ribose is dismantled and parts are attached to the carbon-nitrogen ring to make a 6-membered ring. And the thiazole-P that HMPP is combined with looks a lot like the ring on AIR but with sulfur instead of nitrogen.

Thiamine is part of many complexes and it acts to move carbon chains from one molecule to another. In the Pentose-Phosphate-Pathway Thiamine is one way ribose-5-P is made by moving 2-carbon units between other carbohydrates (carbon with water, hydrocarbons are carbon with hydrogen). Maybe we’re descended from the thiazole?

And while it’s fuzzy on the diagram ThiO/ThiH are two routes to make what looks like glycine, but there’s a double bond on the nitrogen (an imine as opposed to an amine). Like the double bond on FGAM, the molecule right before AIR (and see NADP). There’s some interesting things with glycine similar molecules here and there.

Then there’s NAD(P) (the P is a phosphate that changes Nicotine-Adenine-Dinucleotide’s metabolic role, the 2′ hydroxal, interesting…), a proton extractor/dispenser. It’s effectively the same for electrons. Aspartate is involved again and now it gets an imine before getting combined with DiHidroxyAcetonePhosphate, another glycolysis intermediate before ring synthesis and attachment to ribose.

Then there’s cobalamin (VB12), this molecular monstrosity is a rearranger (isomerase), methyl extractor/dispenser, and halogen extractor. I need to add it but the initial rearrangement of AIR opens ribose like with histidine and Tryptophan, and the 1′ carbon is lost.

Tetra-Hydro-Folate, a methyl (-CH3), methylene (-CH2-), methenyl (-CH=), formyl (-CH=O), or formimino (-CH2=N) extractor/dispenser. This molecule is part of many 1 carbon processes. It dispenses the formate in purine biosynthesis. It’s involved with the transformation of serine to glycine and back. And it’s made from GTP. I’ll add it but the 5-membered ring of GTP is opened first between the nitrogens and the carbon between is lost as formate before ribose opens and all of the ribose is used in following molecules.

Lastly I added a part of Sulfur metabolism, the Iron-Sulfur cluster part that provides the sulfur in the Non-PRPP part of Thiamine biosynthesis in the form of carrier proteins being the sulfur where it is needed. Sulfur chemistry is a big part of this, and yet it’s not very directly involved in nucleic acid biosynthesis. It is critical in cofactors used to move carbon around (Thiamine, Biotin, coenzyme-A…).

PurF has what may be a vestigial iron-sulfur cluster though. Structural Biology of the Purine Biosynthetic Pathway: “The first type, present in higher vertebrates, plants, flies, cyanobacteria, and Gram-positive bacteria, contains a structural Fe4S4 cluster and a cleavable N-terminal propeptide, and is exemplified by Bacillus subtilis PurF in literature [10,16,17].”

Plans.

Add info about proteins and nucleotides as adaptors and dispensers/extractors of other molecules.

Add info about thematic differences among NTPs as P or PP donors.

Add more AARS (aminoacyl tRNA synthetase) info.

Attempt to organize the relationships by intermeadiates, and protein subdomain.

Add the urea cycle due to the connections between Purine (Asp amination), Pyrimidine (CP) and Arginine byosynthesis.

Add more reaction intermediates like aminoacyl-AMP. For example the glycine in purine biosynthesis exists as phospho-glycine. The aspartate as phospho-aspartate.

Other Observations.

Molecular “dispenser/extractor” and “adaptor”.

ATP, THF, glutamate, and other things ultimately may be providing things that were primordially available. So to an extent they, and some protein subdomains of associated enzymes, can be excluded from the picture. In fact aspartate and even glycine itself are ammonia donors in transamination reactions.

Similarly the same exclusion of parts can be done for molecules that act as adaptors, even tRNAs. I have ideas about coenzyme-A without the Adenosine-phosphate used to carry it around the cell.

Ideas.

Pre-cellular life. When looking at the NMPs and NDPs as adaptors the Pyrimidines have seem to have a bias towards membrane components and systems. CDP-glycerol and UDP and this part of bacterial cell wall biosynthesis.

G3P>E4P>R5P progression in backbone = each nucleotide in codon triplet?

Lysine is the only aa with a C1 and C1 AARS. Connection to Lysine looping steps in Lys biosynthesis via symmetry at the codon stem?

Glycinamide and bicarbonate, ammonia, or hydrogen sulfide as significant to abiogenesis.

Ribose originally come from a 3C+2C source? G3P + the activated aldehyde on Thiamine?

Issues.

The medium allows a never-ending cycle of reorganizing by different principals. On one level this is good. Copy and past my way to unpacking metabolism.

Good and Bad. All the things in my visual field is a potential benefit with ADHD. There are drawbacks.

Resources and how I use them.

Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology. 2nd ed. Gerhard Michael and Dietmar Schomburg, 2012. General reference.

Roche free molecular and cell biology posters. Sometimes I like to just stare at the whole mess.

Uniprot. This is a resource for protein sequence and functional information. This was my first stop in getting information about a protein, example PurF. After getting length and other info I scroll down to family and domain databases and check the Interpro links.

Interpro. This is a resource for classifying proteins into families and predicting domains and other important sites. Here’s PurF again. Scrolling down to entry matches for the protein you can see the what domains have been defined so far, 2 subdomains. Once I have the subdomains I go to ECOD.

ECOD. This is a resource that is a “… hierarchical classification of protein domains according to their evolutionary relationship.” Proteins aren’t just related to one another, their subparts are related to one another. Often separately. There are 4 levels of comparison X: possible homology level, H: homology level (big families), T: topology level (structural similarity), F: Families.

The first domain of PurF is in the alpha helixes + beta sheets 4-layers group. X: Ntn/PP2C (N-terminal nucleophile aminohydrolases/Protein serine/throinine phosphatases 2C), H: Ntn, T: Class 2 glutamine amidotransferases, F: GATase_2_1st. You can click right into it.

The second domain of PurF is in the alpha helix/beta sheet 3-layered sandwich group. X: PRTase-like (PhosphoRibosyl-Transferase), H: PRTase-like, T: PRTase-like, F: Pribosyltran.

With these 2 domains and boxes of their close relatives I can look for patterns that suggest general functions of the group, and how they relate to one another. There are many studies looking at relatedness among for example ATPgrasp enzymes and their subdomains.

And with all of these relationships in ribose metabolism visible on the diagram lots of patterns may become visible. It’s like a Rubik’s Cube/Matryoska Doll/Where’s Waldo combo. There are probably multiple Waldo’s.

KEGG. Sometimes it’s useful to look at more specific metabolic pathways. This is also good for finding everything a molecule like uracil might be involved in.

Pubmed. A major archive of journal articles.

Wikipedia. Often a good place to get general info.

Things started feeling different over the last 6 months. And yet parts were very familiar.

“Saturated” maybe? “Overstimulated”? An increase in tension driven by several sources including politics, family, career and more. All of my social parts hurt. And they were interconnected. I could feel the hyper-vigilance coming on. Again. And I was in a place where I was letting my negative feelings hit me so I could understand them better so I just let the hurricane come.

And I did what I did every time before. I reduced my number and kind of social interaction for stability. Especially online. The internet does not feel like meat space. “Reduced” is doing some work because in the past it has been a matter of abruptly stopping interaction with no word to anyone. It’s not that I did not want to tell people that I had to go for a while. I could not process extending social contact, too much negative feeling and its effects on my ability to make responses. I managed to type something in some places this time.

I wish society was better at preparing us for what we are as human beings. This shit makes sense as personality with impulsive elements. I honestly believe we are doing something similar to what we did with left-handed people but with personality. People feel as if they were 7-10 on a 1-10 spectrum even when I feel positive about them. It helps to process alone but this is not something I like.

Relatedly I’ve been getting an understanding of just how old and deep my general social anxiety goes. I know I was an outcast by 1st grade. And sometime in there my ability to extend contact was compromised. Maybe it was always compromised. I can like people, but groups feel negative. I don’t know how much in-group feeling I have. But it’s still perfectly natural human behavior so instrumental control of that is something I have to work on.

And it’s a difficult thing integrating myself with the tourettic version of this, while I’m learning about the structure of feeling and emotion. There are advantages and disadvantages. I don’t know how to generalize that part beyond issues relating to volume and sets of repetitive thought processes. I’m somewhat lost in everyone else.

Right now I’m arguing politics on a local politics board to keep in practice and almost nothing beyond that. It’s not that hard to poke at beliefs and behavior I see as social negatives but I still have to push through something. I can do the social conflict thing. Other things are harder. This blog is often painful.

I’m chipping away at it. It’s just big. And there aren’t guides for a lot of it. I’m pushing to get my family talk politics with me and other things I feel negative about. Avoiding it has resulted in decades of accumulated negative feelings. Feelings that don’t just go away when I am around them. Career is full of negative feeling that I’m trying to figure out and that’s tied to politics at multiple levels including how society utterly fails at neurodevelopmental differences. Family connects to career and politics because Rs. Republicans. My birth culture was not helpful with the science thing.

And still more. There’s a whole subsection where where I’m in a kind of “rumination and introspection mode” with respect to my political behavior. Difficult and useful criticism. I’m preening my tools. I ran into this “gender null” thing that looks interesting as a result. At least the hurricane is interesting so far.

I’ll end by saying that I want to try to blog about the game Gems of War. I need something to practice and I have to process the strong feelings in what I have posted so far. I actually have most of a draft finished. It got hard. I’m hoping that this post helps. If the spawn of Bejeweled and Magic the Gathering sounds interesting to you this blog could stay interesting. It’s what I think I can do for practice.

I was happy to see there are a lot of articles about the subject of stochastic terrorism when I did some looking. Here is one by Mhedi Hasan, After El Paso, We Can No Longer Ignore Trump’s Role in Inspiring Mass Shootings. The article defines it as,

“the use of mass communications to incite random actors to carry out violent or terrorist acts that are statistically predictable but individually unpredictable.”

Trump talks about his political enemies like they are violent threats in addition to the constant lying and other disparaging things. DARVO. The chants to lock people up without any respect for cited crimes or judicial processes are incitement.

Right after the kidnapping attempt on Michigan Governor Gretchen Whitmer we might have one on Wichita Mayor Brandon Whipple. Trump is the best worst example of things right now. In this case how irrational incompetent political leaders can inspire violent acts with broad disparaging language.

Credit to Lynna in PZ’s Political Madness thread.

A feeling is a body sensation.
We feel while we do things, and we feel about things.

I often go to this paper when an opportunity to offer information about, or contrast a popular misconception of feeling and/or emotion comes up. Maps of Subjective Feelings. One specific figure is very useful.

The image from the paper is a map of body feelings reported by a group of people while they were doing or experiencing 100 things. The colors indicate presence and intensity.

I’m going to discuss the categories out of order. I’m sure plenty of people will have criticism about the categorization of individual items or whole categories, I do too. But I want to emphasize the general embodied nature of feelings independent of our ability to categorize them.

Homeostasis is your feeling of of your body’s basic system status. Oxygen, hydration, nutrition…and lack thereof. Your meat computer has wiring for the status, location and integrity of it’s parts. A related part of the nervious system is the “enteroception”, or the parts that have to do with your ability to feel your body. Incoming sensory pathways for skin, meat, bone, organs…

Illness is your feeling of infection, injury, hangover…you feel the damage, chemical driven metabolic change, and reaction to microbial invasion of yourself.

Cognition is your feelings associated with mental tasks and experiencing it as an action. I can feel the increased blood flow in my head, often in specific locations.

Unknown, look for yourself and see what you think. I’m interested in a more general point.

These first four are feelings of yourself as an object. A running biological being of 44 segments if you go by nerve pairs. An apatite mounted tube of eukaryotes.

There is a lot of individual diversity here and things like mindfulness meditation focused on your body would have the effect of increasing the resolution of your feeling of yourself, and that component of emotion.

Feeling and emotion.

Emotion, both positive and negative emotion, is a more complex thing than the mere feeling of the body.

There is a relationship between feeling and emotion. Feeling is in the body, but emotion involves feeling about objects we see, hear (words are objects), touch and experience through “exteroception”, or the parts that have to do with your sensory organs that detect objects outside of yourself. Eyes, ears, skin…

The objects we store in our minds through exteroception are associated with the enteroception feelings we were having while we stored the memory of the object. That includes our bodies as objects making three important categories of feelings:

1. The enteroception feelings associated with our bodies as functioning objects.
2. Our feelings about exteroceptive objects outside of ourselves. Body states recorded as we interact with objects.
3. Our feelings about our bodies as objects. Body states recorded as we interact with ourselves as objects.

That’s how we store our sense of goodness or badness of something, or “valence” in brain science language. Exteroception gets bound to enteroception in memory which lets us have feelings about things.
We feel happy, sad, angry, or fearful about outside objects, other meat computers, ourselves.

We abstract body feelings into feelings about objects which include other meat computers. Feelings are good things, perfectly natural, basic features of consciousness. Emotions which use feelings are likewise perfectly natural basic features of consciousness.

Consequences.

There are many social attitudes and beliefs about feeling and emotion that are producing bad decisions all around us and that should be challenged to reduce irrational and illogical decision making.

As I learn about what we are and how we work I see consequences to it. Some of those consequences affect many common uses of the words feeling and emotion that aren’t consistent with reality and have political dimensions.

Note that I came to these views largely through political confrontations and so they are good for political confrontations and people should be aware of that bias.

“Being emotional”

This seems presented as a bad general category like the person is wrong because they have emotions, usually negative ones. I don’t see people disparaging emotion this way talk about what the feelings in the emotions are attached to. Quotes about the objects the feelings are attached to for example.

The reality is that we are always emotional.

“Unemotional”

The reverse problem is that there is no such thing as “unemotional”. At what time is a person cut off of past enteroception associated with object memory? You don’t stop feeling good and bad about the objects stored in memory.

“Emotional argument”

This is considered a bad thing but all arguments are emotional. I think this is about avoiding what people feel emotional about.

“Feels before reals”

No, “enteroception feels are connected to exteroceptive reals through memory”.

“Emotions X is bad”

General portrayals of emotions and feelings as bad things not only don’t make sense, they are certainly harmful when it comes to understanding and control of yourself as a meat computer, a biological being that binds feeling to objects in memory. I want control all of my feelings as information and tools. This goes for blanket complaints of people feeling offended too.

It gets complicated with things like hate, I’ll admit that up front. But we don’t choose the hate. The hate is bound into the memory. It’s a natural response so I’m more interested in what to do with the hate, fear, disgust, as well as the positive emotions and their associated feelings.

Solutions and Possibilities

A better understanding of how we function when it comes to feeling and emotion is useful on a personal and a social level. In my experience it’s useful when it comes to politically aggressive people because you can redirect to the feelings they are reacting to, and often obfuscating and disparaging about.

It seems simplistic but asking or demanding to see what a bigots feelings are attached to also makes the job of demonstrating the bigotry easier. I like to practice interrogating bigoted disparaging claims. It’s irrational. It’s going to run into an error.

I welcome other observations because this is a social challenge with many pieces and I have one perspective.

Crip Dike is in Portland. They’re participating in the protests and sharing their experiences. You can learn more about the different groups involved, and what it’s like to be tear gassed in a continuing series of posts as events occur.

Start with What do you need to know about the Portland protests?

It’s important see what people actually there are experiencing.

Recently at Pharyngula a commentator mentioned something related to a political problem I’ve been thinking about. The political problem is the attempts to call covid 19 by names related to China or Wuhan and probably other versions.

They pointed out how people from one country would name a disease after another country and specifically the “the French disease”, syphilis. After some searching I found this.

Brief History of Syphilis.

Introduction, second paragraph.

From the very beginning, syphilis has been a stigmatized, disgraceful disease; each country whose population was affected by the infection blamed the neighboring (and sometimes enemy) countries for the outbreak. So, the inhabitants of today’s Italy, Germany and United Kingdom named syphilis ‘the French disease’, the French named it ‘the Neapolitan disease’, the Russians assigned the name of ‘Polish disease’, the Polish called it ‘the German disease’, The Danish, the Portuguese and the inhabitants of Northern Africa named it ‘the Spanish/Castilian disease’ and the Turks coined the term ‘Christian disease’. Moreover, in Northern India, the Muslims blamed the Hindu for the outbreak of the affliction. However, the Hindu blamed the Muslims and in the end everyone blamed the Europeans [4–6].

Anyone who wants to name a disease after a country, region, ethnicity, race and similar are bigots. This is social dominance behavior for no good reason. Racism and other bigotries.

Another version could be naming pranks and irresponsible behavior after other races. When I was a kid a prank some kids did involving knocking on someone’s door and running away was called “n%$$#& knocking”. Knocking someone out by pushing on their neck was called a “Chinese knockout”.

It’s unacceptable. It’s a discriminatory irrational insult and for what? I honestly want to know and I’m going to look for the reason so I can do something with it. Racist, nationalist and similar solidarity is one answer. In addition to desire to make a percieved adversary feel insulted.

I seen people insist that it’s acceptable because that’s where it started. That changes nothing. That’s an excuse to keep doing something insulting. I’ll keep calling it racist, bigoted. Coronavirus for the kind of virus and covid 19 for the specific example.

Finally I’ve considered and rejected calling it something like “the Trump virus” (reflect their behavior back on them). I’ve got the same instincts but I want them attached to better things. I may use that as an example of something that is similarly useless and counterproductive dominance behavior in place of relevant personal characteristics to attach negative feelings to.

I’ve seen this mentioned a few times and it’s very interesting. Healthy habits of thought? I’m not sure quite how to fully define such a thing. I’ve been trying to think of a collection of examples to post about though.

One is something I want to call “therapeutic social isolation” which involves spending time processing things by myself. Processing by yourself and processing around other people are going to feel different and that’s likely to be a good difference to feel. Maybe we have an instinct for such social isolation if we get “overloaded”.

Another thing which is like a version of the first is if I feel particularly intense about a piece of writing, even a text, I do a draft and come back later. Later can be an hour, the next morning, a couple of days… I can’t say how long it takes to move an experience from short to long term memory but a night of sleep can be useful in seeing if you still feel the same.

I’m sure there are many things that can be included in something like mental hygiene. I’m not sure what it looks like as a fleshed out concept but that’s a start.