Posts Tagged ‘ATP’
abiogenesis is heavy, man
So, once more into the breach, let’s try and have fun with abiogenesis. It supposedly starts with organic compounds, generally considered as carbon-based, though I’ve heard tell of the possibility of silicon-based life – presumably you want to start with an element that combines readily with others, and those elements, but carbon in particular, fit the bill. Hydrocarbons, the simplest of which is methane (CH4), are an obvious example. However, as far as I’m aware, we haven’t been able to bridge the gap between non-life and life, inanimate and animate, chemistry and biology, in any clear-cut way in our laboratories and experiments. Membranes, self-replications, chains, autocatalysis are all more or less required, but nobody seems to have any clear idea of how and when it all started here. There may have been a few starts that then ended, until one didn’t. Here’s a bit from Wikipedia:
Life functions through the chemistry of carbon and water, and builds on four chemical families: lipids for cell membranes, carbohydrates for chemical energy storage and structural composition, amino acids for protein metabolism, and the nucleic acids DNA and RNA for heredity. A theory of abiogenesis must explain the origins and interactions of these classes of molecules.
Sounds like hard work, especially the genetic stuff. So I’ll start with amino acids, since I don’t have a clue… We get them from food, essentially, but what is food but living stuff, organic stuff, and so goes the circle. But let’s keep going. They were first discovered/identified in the early 1800s, the first being asparagine, from asparagus, in 1806. Apparently our bodies need twenty types of these carbon-based molecules, strings of which, or chains of which, form proteins. Of those twenty, eleven can be made by our bodies, and are labeled non-essential, while the other nine, the essential ones, must be obtained by food. All in all they’re important for brain chemistry, hormone production, and for maintenance and repair of muscle, skin and organ tissues.
But how did amino acids come to be? And what’s the difference between L and D types of amino acids? Apparently they’re like the mirror image of each other which makes me think of chirality which I barely understand. Britannica starts one of its articles with this:
The question of why organisms on Earth consist of L-amino acids instead of D-amino acids is still an unresolved riddle. Some scientists have long suggested that a substantial fraction of the organic compounds that were the precursors to amino acids—and perhaps some amino acids themselves—on early Earth may have been derived from comet and meteorite impacts. One such organic-rich meteorite impact occurred on September 28, 1969, over Murchison, Victoria, Australia.
… which is interesting but doesn’t help much, though it’s certainly a cause for wonder. Anyway, the video referenced below tells me that of the 20 amino acids that build proteins in our body, 19 are chiral. Then one particular amino acid, alanine, is focussed on, as it’s one of the simplest enantiomers – pairs of molecules that are mirror images of each other, and so un-super-imposable.
So this molecular biology is about life-sustaining molecules but not quite organisms, and nobody knows precisely how complex molecules become organisms – otherwise we’d be having fun creating new life forms, and only gods are allowed to have that kind of fun.
So we haven’t made life yet, but we’re getting there?
I’ve heard of course of an RNA world that might have preceded the DNA one, so let’s go there for a while. Nucleotides, nucleic acids, nucleosides, nucleobases and such all have to be understood and connected together to make sense of it all. So from here on in it will be attempted definition after attempted definition, with further attempts to connect them all together.
So what about prebiotic synthesis? Or, to quote another video referenced below, ‘location… where can we find the satisfactory chemistry required to make bioactive molecules? And what were these first biomolecules? We must surely need water and carbon – that’s what life as we know it requires, at a minimum. Then there’s nitrogen, key to building proteins (amino acids being nitrogen-based), and RNA and DNA for ‘information’. And phosphorous, essential for building many biomolecules, ATP for cellular energy, and phospholipids for cell membranes. Also referenced are amphiphiles (never heard of them) for forming primitive cells. They’re made from phospholipids so I’m not sure of the difference, just as I’m not sure of the difference between lipids and fatty acids – and did somebody mention tryptophan…? You need largely to be there in the labs being educated by the experts, and observing and experimenting.
The discovery in quite recent times of hydrothermal deep ocean vents and the chemo-synthesised, sunlight-free ecosystems they support, has added fuel, such as hydrogen sulphide, to the quest for the earliest life forms. But, to quote Phy the Neutrophil:
In an alkaline vent environment, the conditions for chemistry heavily disfavour the formation of cells. While hydrothermal vents do have the chemistry to make long-chain fatty acids, the harsh salty environment of the ocean is going to make it very difficult for these proto-membranes to form.
Mr Phy likes the Darwinian idea of a warm little pond, but also recognises that this too has its problems. In any case, some kind of cell or capsule formation, however or wherever it may have evolved, would be a major advance. Creating an enclosed micro-environment is likely to speed up the process of effective chemical development, and Mr Phy goes into much detail on this, and its alternatives, but of course I’m not strong on biochemistry, so proton gradients haven’t triggered my neurons.
But I must soldier on. AI has this to say on proton energetics:
All life uses proton gradients across membranes to drive energy production via ATP synthase. Because building proton pumps requires pre-existing energy, scientists propose that life began in alkaline hydrothermal vents, where natural geological pH gradients across inorganic pores provided the first proton-motive force before biological pumps evolved.
Adenosine triphosphate (ATP) , which I know is associated with mitochondria in humans, and is always called the ‘energy molecule’, or the energy storage molecule, as Wikipedia puts it, relies on this ATP synthase enzyme, which catalyses ATP using ADP (adenosine diphosphate) and inorganic phosphate. It gets very complicated with protons being pushed along an electrochemical gradient so that ATP can be stored by cells for future use.
Of course the evolution of ATP synthase, like so much in the make-up of the earliest life forms, is obscurely ancient, but well worth exploring as it appears to be central to all life. Wikipedia goes into hellish detail about it all, which is impressive and exhausting. I’m not sure if I can go on…
References
https://en.wikipedia.org/wiki/D-Amino_acid
https://www.britannica.com/science/amino-acid/Amino-acids-and-the-origin-of-life-on-Earth
how statins work 3: the beginnings of cholesterol, from Acetyl-CoA
So how is cholesterol made in the body? We need to know this in order to understand how statins inhibit or interfere with this process.
I’ve shown the actual structure of cholesterol in part 1 of this series, but remember it’s a sterol, which is a steroid – four carbon rings with hydrogen atoms attached – in which one of the hydrogens is replaced by an alcohol group. The particular form of sterol called cholesterol, with a 7-carbon chain attached to the end-carbon ring (the D ring), and three methyl groups attached to specific carbons in the rings and chain (it’s better to look at the skeletal structure in part 1). There are precisely 27 carbon atoms specifically placed within the molecule.
I’m using a set of videos to understand how cholesterol is synthesised – it might be best to look at them yourself, but I’m writing it all down to improve my own understanding. So we start by understanding something about acids and their conjugate bases. Apparently an acid is a molecule which is capable of donating protons into solution. Take pyruvic acid and its conjugate base pyruvate. Here’s what Wikipedia says about them:
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is a key intermediate in several metabolic pathways throughout the cell.
I don’t understand the first sentence, but no matter, pyruvic acid is a 3-carbon molecule with a carboxylic acid at one end and a ketone group in the middle of the molecule (according to Britannica, a ketone is ‘any of a class of organic compounds characterized by the presence of a carbonyl group in which the carbon atom is covalently bonded to an oxygen atom. The remaining two bonds are to other carbon atoms or hydrocarbon radicals)’. The proton that comes off the oxygen of the alcohol group of the pyruvic acid can be donated into the surrounding solution, increasing its acidity. The pyruvic acid is thus transformed into its negatively charged conjugate base (it’s no longer capable of donating protons but it can receive them). This is the case with all acids in the cytoplasm of cells. As inferred in the quote above, conjugate bases are vital components of biosynthetic pathways. Most of the molecules in the cytoplasm will exist as pyruvate at a physiological pH of around 7.5.
Next – and hopefully this will become clear eventually – we’re going to look at two molecules, NAD+ (nicotinamide adenine dinucleotide) and NADP+ (nicotinamide adenine dinucleotide phosphate). They transport electrons, and are capable of accepting a hydride anion, which is a hydrogen atom with a negative charge. The normal hydrogen atom, called protium, has a proton and an electron only. When it donates away its electron it becomes a hydrogen cation, and when it gains an electron it becomes a hydride anion.
NAD+ is an adenine organic base bound to a ribose sugar. Then there are two phosphate groups coming off the ribose sugar, the second of which attaches to another ribose sugar. This second ribose sugar has nicotinamide attached to it (see below),
in which the phosphate groups are magenta-coloured circles. To explain something about ribose sugars, here’s something from Pearson Education:
The 5-carbon sugars ribose and deoxyribose are important components of nucleotides, and are found in RNA and DNA, respectively. The sugars found in nucleic acids are pentose sugars; a pentose sugar has five carbon atoms. A combination of a base and a sugar is called a nucleoside. Ribose, found in RNA, is a “normal” sugar, with one oxygen atom attached to each carbon atom. Deoxyribose, found in DNA, is a modified sugar, lacking one oxygen atom (hence the name “deoxy”). This difference of one oxygen atom is important for the enzymes that recognize DNA and RNA, because it allows these two molecules to be easily distinguished inside organisms.
So, just for my own understanding, nucleotides include phosphate groups. NAD+ is a dinucleotide, with two nucleotides (ribose sugars with phosphate groups attached), attached to adenine and to nicotinamide molecules. Also, NAD+ has a positive charge around the nicotinamide – on its nitrogen atom.
NAD+ becomes neutralised by accepting a hydride anion (one proton and two electrons) and becomes NADH, or reduced NAD. Now, remembering NADP+, it has an extra phosphate group on the ribose sugar of the adenine nucleotide (also called an organic base, apparently). Like NAD+, NADP+ can accept a hydride anion (becoming reduced NADP) and then later exchange it in another reaction. Effectively these molecules are electron carriers, collecting electrons and transporting them to where they’re needed for other reactions.
Now to introduce something else completely new for me – Acetyl-CoA (acetyl coenzyme A). A quick grab again, this time from Wikipedia:
Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid [Krebs] cycle to be oxidized for energy production
Acetyl-CoA is found, and presumably produced, in mitochondria, and as part of this cholesterol-synthesising pathway it needs to be removed from the ‘mitochondrial matrix’. What’s that, I ask. So here’s a bit about the mitochondrial matrix, from yet another source, this time Study.com:
The mitochondrion consists of an outer membrane, an inner membrane, and a gel-like material called the matrix. This matrix is more viscous than the cell’s cytoplasm as it contains less water. The mitochondrial matrix has several functions.It is where the citric acid cycle takes place. This is an important step in cellular respiration, which produces energy molecules called ATP. It contains the mitochondrial DNA in a structure called a nucleoid. A mitochondrion contains its own DNA and reproduces on its own schedule, apart from the host cell’s cell cycle. It contains ribosomes that produce proteins used by the mitochondrion. It contains granules of ions that appear to be involved in the ionic balance of the mitochondrion.
So basically this matrix is like (or equivalent to) the cell’s cytoplasm, only more viscous, and contains ribosomes, one or more nucleoids and ionic granules, inter alia.
Acetyl-CoA is essential to the biosynthesis of cholesterol, and is found initially in the mitochondrial matrix, and we need to look at the pathway for its removal from that matrix into the cytoplasm, where all the action occurs.
Intruding into the mitochondrial matrix from the (quite impermeable) inner cell membrane are the cristae, which give the membrane more of a surface layer for interactions. This inner membrane is the site of oxidative phosphorylation. What’s that, I ask. Well, it’s key to the production of ATP, and at least I know that ATP is the ‘energy molecule’, and that it’s produced in mitochondria. Here’s something about the process from Khan Academy:
Oxidative phosphorylation is made up of two closely connected components: the electron transport chain and chemiosmosis. In the electron transport chain, electrons are passed from one molecule to another, and energy released in these electron transfers is used to form an electrochemical gradient. In chemiosmosis, the energy stored in the gradient is used to make ATP.
So a strong proton gradient is built up across the inner membrane of the mitochondrion. It’s a concentration gradient but also an ‘electrical potential difference’ gradient, so that the electrical potential within the matrix is lower, by some 160 millivolts, than that across the inter-membrane space. The protons within this space are unable to pass back into the matrix. The only way they can get back into the matrix is by means of ATP synthase which can harness the energy from the protons as they move down the chemical and electrical gradient, and use that energy to bind ADP to inorganic phosphate to create ATP.
I don’t fully understand all that, but the main point here is that the mitochondrial inner membrane is very ‘tight’, which makes it difficult to transfer Acetyl-CoA out of the matrix and into the inter-membrane space, from which it can more easily diffuse through the more permeable outer membrane into the cytoplasm.
The structure of Acetyl-CoA: it consists of an acetic acid molecule (CH3COOH) with a thioester link to the thiol group of a coenzyme A molecule. The importance for us here is this thiol (HS) group, which is similar structurally to an alcohol (HO) group, as sulphur has similar properties to its periodic table neighbour, oxygen. So thiol groups can be linked to carboxylic acid groups as alcohol groups can. Acetyl essentially means acetic acid with the alcohol removed. To get this Acetyl-CoA out of the matrix, it is first bound to oxaloacetate, a four-carbon molecule, to create citrate, the first molecule of the citric acid cycle. This citrate can be passed through the mitochondrial inner membrane and into the cytoplasm where it can be converted back into Acetyl-CoA.
So the conjugate base, oxaloacetate, has carboxylic acid groups, attached to the first and fourth carbon atoms, that have lost their protons into solution. An enzyme within the matrix is able to combine oxaloacetate with Acetyl-CoA and water to create citrate…
Okay, this is proving to be a much longer story than I might’ve hoped, but I like to be thorough – and in reality I’m still not being thorough enough. There’s a lot of rubbish on the internet about statins, much of it self-serving in one way or another, so I’ll just keep plodding along until I feel at least halfway informed about the matter. Meanwhile, you just keep getting on with your work, and don’t mind me.
References
Cholesterol biosynthesis part 1, by Ben1994, 2015
Cholesterol biosynthesis part 2, by Ben 1994, 2015
https://www.britannica.com/science/ketone
http://www.phschool.com/science/biology_place/biocoach/bioprop/ribose.html
https://en.wikipedia.org/wiki/Acetyl-CoA
https://study.com/academy/lesson/mitochondrial-matrix-definition-function-quiz.html