Asparaginase therapy for ALL, biochemistry of asparaginase and asparagine synthetase

Asparagine biochemistry, asparagine synthetase, and asparaginase treatment for ALL.You never know where a scientific exploration will take you - I learned so much about so many different things just by researching single amino acids, and Asparagine (Asn, N) turns out to be one of those story-starters. Yes, the name does come from asparagus, but that’s not the big story I want to tell you about. Today is ALL about Asn & how childhood Acute Lymphoblastic Leukemia (ALL) has an “Achille’s heel” for it that is targeted in mainstay treatment.

blog form: http://bit.ly/asparagineasparaginase

It’s Day 17 of #20DaysOfAminoAcids - the bumbling biochemist’s version of an advent calendar. Amino acids are the building blocks of proteins. There are 20 (common) genetically-specified ones, each with a generic backbone with 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/aminoacidstoproteins but the basic overview is: amino acids have generic “amino” (NH₃⁺/NH₂) & “carboxyl” (COOH/COO⁻) groups that let them link up together through peptide bonds (N links to C, H₂O lost, and the remaining “residual” parts are called residues). The reason for the “2 options” in parentheses is that these groups’ protonation state (how many protons (H⁺ ) they have) depends on the pH (which is a measure of how many free H⁺ are around to take).

Those generic parts are attached to a central “alpha carbon” (Ca), which is also attached to one of 20 unique side chains (“R groups”) which have different properties (big, small, hydrophilic (water-loving), hydrophobic (water-avoided), etc.) & proteins have different combos of them, so the proteins have different properties. And we can get a better appreciation and understanding of proteins if we look at those letters. So, today let’s look at Asparagine (Asn, N).

Asparagine (Asn, N) is the “cousin” to the amino acid we looked at yesterday - Aspartate (Asp, D). http://bit.ly/aspartateshuttle

Unlike Asp, which is negatively-charged under usual bodily (physiological) conditions, asparagine is neutral. But they look a lot alike - and as we’ll see, our bodies can convert between the two of them. Both have a methylene (-CH₂) followed by a carbonyl (C=O) in their side chain, but they differ in what’s attached to that carbonyl C on the other side. Asp has another O, giving it a “carboxyl group” but Asn has an amino group (-NH₂) instead. This makes Asn the AMIDE of Asp. AM I DEscribing something without defining the jargon? I’ll fix that - and tell you more about Asn biochemistry - after I tell you a story about it (don’t worry, you don’t need to know the nomenclature stuff for it)).

Asparagine is considered nonessential in the dietary sense of the word - our bodies can make it. But they can also break it, and they can use it to build other molecules (this can be joining up with other peptides to form big ole proteins, or getting modified to form other small molecules). So the levels of free Asn in your body at any time depend on how much of it you eat, how much you make, how much you break, & how much you “siphon away.” Your body keeps a nice balance by regulating the making, breaking, and other-purpose-using.

In a type of blood cancer called childhood Acute Lymphoblastic Leukemia (ALL), the balance gets thrown off because the cells lose their ability to make it as much, but they still need it, so they rely on a steady source of “pre-made” Asn from the bloodstream. This has led to a therapeutic strategy of depriving these cells of what little Asn they do have by adding extra “breakers” into the bloodstream, depleting the Asn supply - this strategy selectively affects the cancer cells because the other cells have enough “makers” to counterbalance these “breakers”

So let’s meet these molecular workers, which have the general job description of “enzymes.” An enzyme is a reaction-speed-upper - it’s usually a protein, sometimes a protein/RNA combo, sometimes RNA alone, and it helps mediate reactions by doing things like bringing reactants together and holding them in the right orientation with the right ambience, etc. You know you’re probably dealing with an enzyme if you see the ending “-ase”

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