MSG? Fine by me! It’s just a salt of glutamate, so why does everyone gotta hate? From giving food its rich umami taste, to helping your cells safely remove nitrogenous waste, there’s a lot to love about this protein letter, so today I want to help you get to know it better! It’s more “popular” for its role as a brain messenger, but for those functions to brain experts I shall defer – instead, I hope you won’t become irate if I focus on some of the other (just if not more so) vital functions of glutamate (Glu, E)!
It’s Day 19 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.
Glutamate (Glu, E) is best known for its role a a neurotransmitter – a brain signaling molecule that nerve cells (neurons) use to communicate to other neurons. Want to send a message? – ship out some glutamate into the space between the cells (synapse) and that glutamate will bind to special receptors on the other cell, channels will open, and ions will rush in, leading to a change in charge that makes other channels open easier, sets off signaling cascades, etc. It’s cool stuff – but so many people find it cool that its role as an excitatory neurotransmitter tends to get all the spotlight. So today I want to tell you about some of the other aspects of glutamate that are just – if not even more – important, yet are way further down the search results if you Google it.
Glutamate isn’t just important for neurons – it’s important for ALL our cells – really important – because it’s one of the key ways we can recycle amino acids while safely handling the nitrogen part. I’m going to tell you about this key role in transdeamination in a minute, but first I want to address something that might show up along with the brain stuff in your google search – I’m talking about the “MSG added to food causes all sorts of symptoms like headaches, racing heart, tingling limbs, etc.” myth.
MSG stands for MonoSodium Glutamate and it’s just the sodium salt of glutamate. It gets added to food sometimes because glutamate is responsible for that rich “5th flavor,” umami. Salt’s just another name we give to a neutral ionic compound – ions, by definition, are charged, thanks to their imbalance of protons & electrons (more below). So in order to get a salt you have to have a positive thing(s) (cation) and a negative thing (anion) – but you can mix and match. Stick a sodium ion (Na⁺) with a chloride ion (Cl⁻) and you get NaCl, or as you might know it better, table salt. If, instead of a chloride ion you stick the sodium with a glutamate anion, you get monosodium glutamate (MSG). Add in some disputed science and xenophobia and you get the myth that MSG causes a variety of strange symptoms.
I’m not just going to tell you it’s not true – it isn’t, but I want you to really understand what’s going on – especially since part of the reason the whole MSG myth has flourished is because of misunderstanding and chemophobia fueled by commercial opportunism (i.e. if it has a weird chemical name it must be dangerous so we’ll not use weird names on our labels). Remember dihydrogen monoxide is just a fancy name for water (and, for the lab nerds out there, DTT by any other name would still smell just as eggy) so don’t let companies profit off chemophobia!
Please note that I am in no way judging people for being misled – I recognize that chemistry knowledge is an immense privilege that not everyone has a chance to gain which is why I want to help share it with others. And I’m also not saying that all chemicals are good in all contexts – I just think it’s important to not immediately equate “chemical” with “bad”. Thank you for coming to my TED talk…Steps off soapbox to continue telling you about MSG – or, let’s spell it out why don’t we – MonoSodium Glutamate
My first task – convince you that chemistry is really really really cool! It’s like a magical molecular dance underlying everything, so let me introduce you to some of the key players. Biochemical molecules are a bit like LEGOs – from carbohydrates (simple sugars like glucose to more complex storage forms like starches, glycogen etc.) to lipids (fats, cell membrane pieces, etc.) to proteins and even mixtures of them – glycoprotein anyone? – they’re all made up of the same kinds of pieces – atoms. Atoms are the basic units of elements – think black LEGOs vs. blue LEGOs except that, instead of colors, the difference between elements (e.g. carbon (C) vs nitrogen (N)) is the # of protons they have.
Protons are little positively charged things & they’re one of 3 key subatomic particles – they hang out with neutral neutrons in a dense central atomic nucleus and then negatively-charged electrons (which have an equal but opposite charge despite being itty-bitty-er) whizz around them in an electron cloud. You can never know exactly where an electron will be – but there are places they most like to hang out, which we call “orbitals.”
At the physical chemistry (p-chem) level, it’s not really like this, but it can be really helpful to think of electron orbitals as “shells” or onion layers. The periodic table is like a “menu” of all the known elements – as you look down a column (these columns are frequently called groups or families), you add a layer but keep the same number of electrons in the outermost shell in the element’s neutral form – and, conveniently, that # is the same as the column # (i.e. carbon is in the 4th column (of the main groups of the table) & it has 4 valence electrons in its neutral form whereas nitrogen, in the 5th column has 5, & oxygen, in the 6th column has 6). These outermost electrons are called valence electrons – they’re the most energetic and, being furthest away from the positive pull of the nucleus, they’re “least loyal” to the atom they come from, and more liable to interact with electrons of neighboring atoms and even leave altogether.
Why would they want to do that? For reasons outside the scope of this post, atoms are usually most stable (and thus happiest) if they have a full “outer shell” like the elements in the last column (the Noble gases) do – for most of the elements we commonly deal with in biochemistry, this means having an octet – 8 electrons in the outer shell (an exception is hydrogen, which only wants 2 because its outer shell is an inner shell for everyone else (except helium). Hydrogen only has a single proton, so you can’t expect it to reign in a ton of electrons! In fact, H often has trouble controlling the single one and, when it loses it (like if it leaves a covalent bond without it) you’re left which just a proton (and a neutron) which is why we often refer to H⁺ as a proton. Note: we call proton donators acids and proton acceptors bases, as will come into play later.
As you can see by the little ⁺ in our proton example, if a neutral molecule loses an electron, # of protons > # electrons, so it becomes positively-charged (cationic) and if a neutral molecule gains an electron, # of protons < # of neutrons, so it becomes negatively-charged (anionic). “Ionic” just refers to a charged thing and things usually don’t really want to be charged. So there’s this kind of compromise atoms have to make about getting that full outer shell vs becoming charged and what decision they make has to do with things like how close they are to full and how well they can handle the charge (for example, communal electron sharing through “resonance” aka “electron delocalization) like occurs in carboxylate ions as we’ll look at, helps)
If they do decide to go charged, they commonly also get “help” from other molecules – since opposite charges attract, cations are attracted to anions & vice versa – so even when Na (which has one electron it doesn’t want in a shell all to itself) gives up an electron to Cl (which just needs one to complete its shell) to give you Na⁺ & Cl⁻, those ions hang out together through an “ionic bond” which is really just a strong attraction – unlike covalent bonds (like those linking together amino acids) which involve electron sharing (i.e. orbitals unite!)
Glutamic acid is the neutral form of Glu and, like aspartic acid (Asp, D), it’s capped off by a carboxylic acid group -(C=O)-OH (the difference between Glu & Asp is that Glu has a longer linker (2 methylene (CH₂) groups versus one). So Glu & Asp have a second carboxyl group (the first being in the generic backbone part but getting lost during peptide bond formation (amino acid letter linking). As the name “acid” implies, they’re willing to give up a proton – sometimes…
Willingness to give up a proton (acid strength) is characterized by the pKa, which tells you the pH at which half of the thing will be protonated – above the pKa, there are fewer protons around, so the thing is more likely to deprotonate whereas below the pKa there are more protons around, so it’s likely to be protonated. Protonation is reversible so the deprotonated form can “change its mind” – act as a base and take a proton – thus we can call the deprotonated form of an acid its “conjugate base” and, by comparing the pKa to the pH you can predict which form will dominate.
Glutamate and aspartate are the conjugate base forms of glutamic acid & aspartic acid, respectively. It’s important to remember that context matters, so the pKa of free glutamic acid and free aspartic acid will be different than when they’re in proteins being influenced by their peers, but with their pKas of ~ 3.7 (Asp) & 4.3 (Glu), they tend to be in their deprotonated (-ate) forms at physiological (normal bodily) pH which is around 7.4. And, having lost a proton while keeping H’s electron, they now have more electrons than protons, so they’re negatively-charged (anionic).
So, remove a proton from glutamic acid and you get glutamate. Stick a sodium ion with it so it’s +1 charge can balance out glutamate’s -1 charge and voila – you’ve got yourself the salt monosodium glutamate. Which might just be one of the only molecules that can sound “scarier” in its abbreviated form than its full chemical name.
How’d it come to sound scary? You know the bumbling biochemist would want to know! The term umami was given to the rich, savory tase associated with foods like meats, miso, and seaweed by the Japanese chemist Kikunae Ikeda. He came up with a process for purifying the source of this umami, glutamate, from seaweed, mixing it with table salt which allowed sodium to help stabilize it by balancing out glutamate’s charge. He called this product Aji-No-Moto. “essence of taste” and patented his process. In the 1920s, the Chinese started making it from wheat instead (and they called it Ve-Tsin) and then, in order to make more of it more easily, scientists started getting bacteria to synthesize it for them.
After Rachel Carson’s “Silent Spring” came out, people started to worry more about chemical additives in their food. And then in 1968, a well-respected journal, the New England Journal of Medicine, published a letter from a doctor who’d eaten at Chinese restaurants, experienced some weird symptoms, and suggested that one cause could be MSG. That suggestion was enough to get other people to write in, newspapers to publish attention-drawing articles, and the whole myth to take off, aided by “cultural construction” – drawing on negative stereotypes of Asian countries as “dirty” and leading to the term “Chinese restaurant syndrome.”
But, MSG is in much more than just Chinese food – it’s in canned food, soups, processed meats, etc. and LOTS of scientific studies have since been done and have shown that MSG is safe. And studies have found that people that think they have a sensitivity to MSG don’t report symptoms if they don’t think they’re eating food that has it. While some people might actually have a sort of allergy to it, what most people experience is more likely the nocebo effect (the opposite of the placebo affect – you experience *real* symptoms based on a false premise). And false beliefs are hard to break.
Now let’s look at some of the other reasons to love, not hate, glutamate! As I mentioned before, biochemical molecules are a bit like LEGOs – there are different pieces you can connect in different ways to build different things and you can break down (partly or fully) things you’ve made and then reuse the parts to build other things. We call such making and breaking metabolism – anabolism refers to the building up (think about the anabolic steroids some athletes take (but shouldn’t)) whereas catabolism refers to the breaking down.
If you look at proteins, you see a lot of “blue LEGOs” because protein letters (amino acids) have nitrogen in their generic backbone part (and some amino acids have additional nitrogens in their unique side chains). But if you look at your basic carbs & lipids, you don’t see “blue LEGOs” – they don’t typically have N in them, so if you want to make carbs or lipids from proteins, you have to remove the Ns – when N is attached to hydrogen(s) we call it an “amine” so we can call N removal deamination. And glutamate plays a key role in making sure this is done safely (if you just break off N as ammonia (NH₄⁺) without doing anything with that ammonia it can cause problems).
Glutamate helps with deamination through a 2-step process called transdeamination. First, in the TRANSAMINATION step, an amine group is transferred from an amino acid that’s getting broken down to a-ketoglutarate with the help of a protein enzyme (reaction mediator) called a transaminase or aminotransferase. AKA 2-oxoglutarate (2-OG), α-ketoglutarate is “just” glutamate with a carbonyl (C=O) group instead of an amine group. So if you swap the carbonyl for an amino by TRANSfering the amino group from amino acid to α-ketoglutarate, you’re left with glutamate and an “α-keto acid” (“keto” refers to having a ketone group (a carbonyl (C=O) attached to carbons on both sides & the “acid” refers to the carboxylic acid part (the same one that makes amino acids acids) & the exact α-keto acid you’re left with depends on what you stole from).
There are transaminases for all the amino acids except lysine & threonine. They all pass off to α-ketoglutarate to give you glutamate, and they all require pyridoxal phosphate (PLP), that vitamin B6 derivative we saw before, in our lysine post, to serve as an intermediary amine holder (i.e. pass it off to PLP that’s held by the enzyme and then pass it from PLP to α-ketoglutarate). Also, note that these work both ways, so you can also use these enzymes to make amino acids. If you want to learn more about how they do it: http://bit.ly/2PERMNF
At this point you might be wondering – why the heck did we do that? what did we accomplish? we removed a nitrogen group from one amino acid, successfully breaking that down, but now we made a new amino acid?! The key thing is that, regardless of what amino acid you started with, you’ve made the *same* new amino acid – glutamate. So you’ve collected the amine group from various sources into the same common carrying molecule – glutamate – so when you get to the actual removal, there’s only a single type of molecule that the remover has to be able to work with.
In the second step, OXIDATIVE DEAMINATION, the amine group can get cut off as ammonia – wait, isn’t this what we were trying to avoid all along?! The key is that the ammonia is now released in a controlled fashion into the awaiting arms of the urea cycle which is concentrated in the liver. Similarly to how recycling gets collected and taken to a central processing factory, the liver is the only organ with a complete “urea cycle” which can combine the ammonia with bicarbonate HCO₃⁻ and then it into urea, which is a less toxic nitrogenous waste product you can just pee out.
Oxidative deamination is catalyzed by glutamate dehydrogenase. As the “oxidative” part of the name suggests, this involves redox – the loss of electrons by one molecule (oxidation) and the gain of those electrons by another molecule (reduction) (remember OIL RIG – Oxidation is Loss (of electrons) & Reduction is Gain. And check out this post:http://bit.ly/2R3vIPf for more). In this case, the giver is glutamate, which gets oxidized to α-ketoglutarate & and the taker is NAD or NADP, which gets reduced to NADH or NADPH.
The reaction is reversible and the NADP form is used in the making glutamate direction whereas the NAD form is used in the breaking glutamate direction. A cool thing about glutamate dehydrogenase is that, while it does not require ATP, it is regulated by it – when ATP levels are high, the cell knows it has plenty of energy so it can focus on building instead of breaking, so the glutamate-making direction is favored. But when ATP levels are low, breakdown is favored.
You can also use glutamate to make glutamine (the amide form of glutamate, which has an NH₂ group instead of an O/OH attached to the carbonyl in its cap). This *does* require ATP money and is helped along by the enzyme glutamine synthetase. In addition to giving you a source of glutamine for protein-making and stuff, this can serve as an alternative to the urea route – the glutamate you get from transamination can be made into glutamine and taken to the kidneys where it gets deamidated by glutaminase to give you back glutamate, which can then be deaminated by glutamate dehydrogenase which, releases NH₃ which, instead of getting used for urea making (we’re in the kidney now, remember) gets used to sop up extra protons to give you NH₄⁺ and maintain pH balance.
Glutamate gets its name from the flour-strengthening protein gluten, from which Ritthausen isolated glutamate from wheat flour in 1886.
how does it measure up?
systematic name: 2-Aminopentanedioic acid
coded for by: GAG, GAA
chemical formula: C5H9NO4
molar mass: 147.130 g·mol−1