I know it’s not tis *that* season, but would you be my Valine-tine? Today in #20DaysOfAminoAcids, another protein letter to fall in love with! And with 3 times the carbon as Ala’s chain, there’s 3 times as much to love! Unless this hydrophobe winds up on the surface of proteins, where it can cause diseases like sickle cell anemia… But in addition to branching off on that segue, I’ll discuss branched chain amino acids (BCAAs) and why it’s “essential” to read this post… erm, I mean it’s essential to eat valine…
It’s Day 3 of #20DaysOfAminoAcids – the bumbling biochemist’s version of an advent calendar. Amino acids are the building blocks of proteins. There are 20 (common) ones, each with a generic backbone to allow for linking up through peptide bonds to form chains (polypeptides) that fold up into functional proteins, as well as unique side chains (aka “R groups” that stick off like charms from a charm bracelet). Each day I’m going to bring you the story of one of these “charms” – what we know about it and how we know about it, where it comes from, where it goes, and outstanding questions nobody knows.
More on amino acids in general here http://bit.ly/2P0pJrB
But today the bumbling biochemist puts in a valiant effort to tell you about valine and convince why it’s of great value!
Day 1 we looked at glycine (Gly, G) which just had a teeny-weeny H (hydrogen) as its R group. Then yesterday we stepped up in size with the next-smallest, Alanine (Ala, A) which had a methyl (CH₃) group for an R. Add 2 more methyl (CH₃) groups branching off the end of yesterday’s amino acid alanine (Ala, A) & you get VALINE (Val, V), BUT it’s not quite that simple. In fact, unlike Ala, our bodies can’t even make Val at all – it’s an “essential” amino acid meaning we need to get it from food. (don’t confuse essential in the dietary sense for essential in the biological sense – when we say amino acids like alanine are “nonessential” we aren’t saying we don’t need them, we’re just saying that we don’t need to get them “pre-made” in our food because our bodies can make (synthesize) them from other molecules we eat and/or break down. (we’ll talk more about this later in the post)
It’s a lucky coincidence that the side chain (aka R group – the “unique part” of an amino acid) of V is shaped like a V! The name actually comes from the related valeric acid, whose name comes from the valerian plant it’s found in. Speaking of finding it – let’s start by talking about how it was discovered – a half-century-long saga of how its structure was uncovered!
This holiday classic to be (if I get my say…) begins back in 1856 with a chemist named von Gorup-Besanez who wanted a glance at the chemicals in glands. He minced up some pancreas and extracted stuff out of it. He found the amino acids leucine and tyrosine (the ones he was looking/testing for) but he also found something that behaved a lot like leucine but was less soluble in boiling alcohol. He figured out the empirical formula C₅H₁₁NO₂ – so he knew the thing he’d found was made up of carbon, hydrogen, nitrogen, & oxygen – and he even knew how many atoms each there were compared to one another, but not how those atoms connected. https://doi.org/10.1021/cr60033a001
In the 80s (the 1880s that is) other groups found it in albumin and sprouts of Lupinus luteus and Vicia stativa. So it was found in a variety of places, but those scientists didn’t try to find out the linkages. Other scientists did. But they all had a hard time figuring out how the atoms were hooked up. Was it 3C in a row? 1 and 2? Was the nitrogen stuck to the end of 1 long chain?
So basically most of the first half a year of research on what we now know as valine was different chemists synthesizing different possible linkages and then comparing how those compounds behaved compared to the real deal Gorup-Besanez had found in the pancreas.
But they were still having problems because their synthesis products contained a mix of stereoisomers. Yesterday we saw how alanine, unlike glycine is chiral – meaning it has non-superimposable mirror images (like your right & left hands). Glycine is not chiral because it has 2 of the same thing sticking off its central carbon (Cα) and you need 4 different things to be chiral. But all the other amino acids, including valine, have those 4 different things, so they are chiral.
In 1906, thanks to new separation techniques (the ester distillation method to be technique-ical, Fischer was finally able to separate the stereoisomers of lab-made possible linkages, and nail down the correct linkage. From thenceforth the name “valine” would refer to α-aminoisovaleric acid. Fischer went forth to do a lot more work on amino acids and synthesizing peptides, despite doing some of those “never do this in the lab” things – he did a taste test. And he found that, in addition to rotating light differently, the L & D stereoisomers of valine taste different. Specifically, d-valine is bittersweet, whereas l-valine is all-the-way sweet.
Where in proteins do you find it? Val, like Ala, is HYDROPHOBIC (water-avoiding) because its side chain just has C’s & H’s which share their shared electrons pretty fairly, so there’s an even distribution of electrons (negatively-charged) that’s nicely matched by the positive protons in the atoms’ nuclei around which the electrons are wizzing. So the charge cancels out everywhere and we say that Val is “nonpolar.” V’s even MORE hydrophobic than Ala because it has a larger nonpolar (evenly-charge-distributed) surface (3 C’s to Ala’s 1).
This doesn’t go well with the very polar water surrounding proteins, which, thanks to the extreme electron-hogging (electronegativity) of oxygen has a major charge imbalance (with the O partly negative and the H’s partly positive). Opposites attract, so the partially-charged parts of water molecules are attracted to other water molecules and to other partly or fully charged things. But nary a charge valine does bring… As a result, water forms interaction networks that exclude valine and other nonpolar things. This “hydrophobic effect” leads to proteins folding up so that nonpolar residues like valine are hidden away in the protein’s core while the hydrophilic (water-loving) ones stick out on the surface. http://bit.ly/hydrophobesarenotafraid
Years and years of evolution have helped “design” (through the random trial and error we call natural selection) proteins with sequences that can fold so that the polar ones are exposed & nonpolar ones are hidden. But with big ole proteins that can be tricky – like trying to work out a seating arrangement for a huge wedding where some of the people don’t want to be near other people & you’re having to seat people as they arrive.
So a single mutation can mess it all up. And this is what happens in the blood disorder sickle cell anemia: a substitution (letter-swap) from the hydrophilic (water-loving) glutamate to the hydrophobic valine on the surface of the oxygen-carrier hemoglobin causes this painful and life-threatening condition because Val, finding itself on the surface when it wants to be hidden, seeks out shelter in the hydrophobic pocket of another hemoglobin molecule. This leads to chains (polymers) of hemoglobin forming that misshape red blood cells which can then get stuck in small blood vessels, restricting blood flow. You can learn a lot more about sickle cell anemia and related disorders (and a potential new gene-editing treatment that’s been in the news) here: http://bit.ly/sicklecelldiseases
UNLIKE Ala, which loves to form helical structures (Ala wins the “most likely to form an α-helix” prize), V does NOT. Val’s branching & bulkiness close to the backbone restricts its backbone angles, making it hard to contort into helices (so Val’s not going to be joining the protein circus anytime soon.
The branching also makes it hard to break down. Valine is one of 3 Branched Chain Amino Acids (BCAAs) – the other 2 are Leucine (Leu, L) & Isoleucine (Ile, I) which I’ll tell you about in the coming days.
Breakdown of all 3 of these BCAAs follows the same pathway and uses the same enzymes (reaction speeder-uppers, usually proteins, that help make reactions happen by holding reactants together and in the optimal position, etc.) in the first few steps. But depending on which you start with, you’ll get different products out that can join up with different pathways at different steps.
Metabolism (the making and breaking of biochemicals in your body) is often described as pathways but it’s really more like a giant subway network where thing can meet up at shared stations and “switch tracks.” So even though we can’t make valine, we can make other stuff with it, but we have to break it down partly into usable pieces.
The 1st step is removing the nitrogen – if you look at the structure of sugars and fats, you won’t see nitrogen there. So if you want to make those things from it (get on board on of those subway trains) you’ll have to ditch the N. And this is accomplished by Branched-Chain AminoTransferase (BCAT). You don’t just want to chop off the amine group to make ammonia (NH4+) because that’s toxic to your cells. Instead, if you want to get rid of that nitrogen you’ll have to pass it off carefully from molecule to molecule until you can ditch it in your pee as urea.
The first pass-off comes from BCAT transferring the amine from a BCAA like valine to α-ketoglutarate. α-ketoglutarate is one of the products of the citric acid cycle (TCA) which is part of the sugar breaking down process. It’s basically the amino acid glutamate but with a carbonyl (C=O) instead of an amino group. So if you swap those out you get glutamate. The BCAA provides the amine for the swap and BCAT helps with the transfer. The glutamate can then go off and get rid of the nitrogen through the urea cycle (or it can be used as glutamate).
And the leftovers, the deaminated BCAA, having lost its amino is now no longer an amino acid – instead it’s a branched-chain α-keto acid (BCKA). In the case of valine, you get α-ketoisovalerate (KIV). The “keto” refers to “ketone” which is a carbonyl (C=O) hooked up to carbons on either side (so -C-(C=O)-C-). It gets to keep the “acid” part of its name because you haven’t touched the carboxylic acid group.
These α-keto acids can then go through further processing with the help of the Branched-Chain α-keto acid dehydrogenase (BCKDH) complex. This complex has multiple copies of several enzymes (it has to do several things so it’s more like a factory assembly line than an individual robot). BCKDH has multiple copies of BCKA decarboxylase, dihydrolipoamide acyltransferase, and dihydrolipoamide dehydrogenase. Genetic defects in any of these enzymes can cause a metabolic disorder called maple syrup urine disease which I plan to cover when talking about one of the other BCAAs…
KIV can be further processed to give you succinyl-CoA, a 3-carbon intermediate of the citric acid cycle that’s part of the sugar-making process. So Valine is GLUCOGENIC – we can make glucose (blood sugar) from it)
how does it measure up?
chemical formula: C5H11NO2
molar mass: 117.148 g·mol−1
aka: 2-Amino-3-methylbutanoic acid
coded for by: GUU, GUC, GUA, and GUG