Amino Acids: The Building Blocks of Proteins

While I've written many posts describing signaling pathways and cellular phenomena of significant complexity, I'd like to use this post to take a step back and look at some fundamental building blocks, first turning to amino acids, the monomers that, when polymerized, make up polypeptides and proteins. At the most basic level, amino acids are really a rather simple chemical compound, consisting of a amino group, a carboxy group, a hydrogen, and a side chain, all sticking off a central carbon atom.  These amino acids are polymerized via their amino and carboxy chemical groups to create long, linear linkages.

Brief aside: In my chemistry class in undergrad, my TA helped us remember the order of the chemical bonds following polymerization by saying N-H, C-H, C-O, N-H, C-H, C-O, ...


You may remember briefly from any stint in chemistry class that a carbon atom that is covalently bound to four different chemical entities (in this case, a side chain, a hydrogen atom, a carboxyl group, and an amino group) can take two different conformations, depending on how these bonds are spatially oriented.  In the case of amino acids, the vast majority of amino acids found in our bodies and used to generate proteins are L stereoisomers.  This is a result of the amino acid synthesis machinery structure exclusively generating L amino acids.  There are exceptions, but we won't get into that.

As I mentioned, amino acids have a side chain: the part of the amino acid that endows it with its identity.  These side chains can be broken into a few groups that we will explore now:

The first set of side chains is the nonpolar, hydrophobic side chains.  The amino acids in this group include alanine, valine, leucine, isoleucine, glycine, methionine, and proline (structures shown to the right).  What you'll immediately notice is that these amino acid side chains are composed mostly of hydrogens and carbons.  Thus, these side chains do not contain polar covalent bonds and do not interact as readily with water (thus the term hydrophobic - they're "afraid" of water.  Some amino acids of note in this group are proline, which contains a ring structure that creates a "kink" in the amino acid, and methionine, which contains a sulfur atom.

The next set is composed of the aromatic side chains, which includes phenylalanine, tyrosine, and tryptophan.  These amino acids all contain an aromatic ring, which makes them relatively nonpolar; thus, they do not interact favorably with water.  These amino acids are involved in mediating protein protein interactions and are frequently found at the active sites of enzymes.

Next up: polar, uncharged side chains: asparagine, cysteine, glutamine, serine, and threonine.  These amino acids contain hydroxyl, sulfhydryl, or amide groups that mediate interactions with water, but they carry no net charge.  An amino acid of note in this family is cysteine, which can react with itself to form cystine, which is important in mediating the formation of disulfide bonds in protein structures.

We'll consider basic side chains next.  These amino acids consist of arginine, histidine, and lysine, which all carry a net positive charge in solution.  Of note, histidine is commonly found at the active site of enzymes to serve as a protein donor or acceptor.

Finally, we find acidic side chains: aspartate and glutamate.  In solution, these amino acids carry a negative charge and are considered acidic.

In the diagram at right, I've drawn up each of the amino acids along with their three-letter and one-letter codes.  These codes are frequently used to abbreviate long lists of amino acids.

Another brief aside:  Did you know that a single woman designated the amino acid abbreviations?  She chose letters that made sense for most amino acids (as you can see above).  For tryptophan, for example, she chose W because she envisioned saying tryptophan as twyptophan.  Kind of cool, huh?


As a summary, here are the amino acid abbreviations:

• A, ala, alanine
• C, cys, cysteine
• D, asp, aspartate
• E, glu, glutamate
• F, phe, phenylalanine
• G, gly, glycine
• H, his, histidine
• I, ile, isoleucine
• K, lys, lysine
• L, leu, leucine
• M, met, methionine
• N, asn, asparagine
• P, pro, proline
• Q, gln, glutamine
• R, arg, arginine (think aRRRRginine)
• S, ser, serine
• T, thr, threonine
• V, val, valine
• W, trp, tryptophan (tWWWyptophan)
• Y, tyr, tyrosine

So there you have it: 20 amino acids.  In addition to these amino acids, our bodies contain several more, including selenocysteine (identical to cysteine but containing selenium rather than sulfur) and ornithine (remember this from glycolysis?).  Amino acids can also undergo modifications: for instance, lysine residues can be acetylated.  More amino acids and their variants are always being discovered as well.

Now that we have the building blocks of proteins established, the next blog post will focus on how these amino acids can be combined (polymerized) into long structures that make up polypeptides and proteins.

The Basics of Protein Translation

Proteins, a major constituent of the cell, have many diverse functions and are classically considered to be the "work horses" of the cell.  Additional molecules, such as RNAs and lipids, have shown importance in signaling and catalyzing chemical reactions; however, proteins remain an important part in the life of a cell.

Before proteins can perform their evolved functions, they must be synthesized within the cell.  The process of synthesizing a protein is critically important to the cell and, thus, is an energy-intensive process.  

The basic building blocks of a protein are amino acids, which come in twenty (and more) flavors.  These amino acids have different properties that afford proteins different structures and functions when the amino acids are polymerized together in distinct orders.  These amino acids can have distinct signaling roles when they exist as monomers as well (see this paper by Nobukuni et al for an example).  

Monomeric amino acids in the cellular environment do not randomly polymerize to form proteins.  In the first of several steps, tRNAs are charged: they are covalently linked to amino acids via aminoacyl tRNA synthetases.  These synthetases hold the very important role of attaching the appropriate amino acid to the appropriate tRNA.  Because inappropriate charging of tRNAs would lead to misincorporation of amino acids into a protein chain (wasting energy or leading to even bigger problems for the cell), sythetases are very specific.  In fact, some synthetases have an editing site, where they will catalyze the removal of incorrectly placed amino acids.

After tRNAs are charged with their appropriate amino acids, they are ready for interaction with the ribosome.  Ribosomes are large, complex molecules that merit their own post.  Briefly, ribosomes are composed of RNA and protein and are made of two distinct complexes: the large and small subunits (depending on the origin of the ribosome, the subunits have different sedimentation coefficients, so you might see 30S and 50S for bacteria or 60S and 40S for eukaryotes, for example).  Ribosomes catalyze the polymerization of amino acids into proteins.

In the first step of ribosome-mediated protein production, the small subunit of the ribosome combined with a tRNA for methionine (the amino acid that begins the protein chain) scans along the transcribed mRNA until it encounters a start site (ATG codon).  Here, the complex stops, and the charged tRNA with its amino acid comes into contact with the peptidyl transferase site (P) on the ribosome.  eIF2 (eukaryotic initiation factor 2), which was along for the ride, hydrolyzes GTP to GDP at this point such that the ribosome stops at the appropriate codon.

Next, the large subunit of the ribosome binds the small subunit, making a full ribosome that is ready for catalysis.

The tRNA that lines up with the mRNA's next codon then binds in the acceptor site (A), along with the help of eEF-1 (eukaryotic elongation factor-1), which hydrolyzes GTP to GDP.  At this point, the ribosome goes into action: using the peptidyl transferase center (PTC), it catalyzes the covalent linkage of the first and second amino acids.

The entire ribosome now moves along the mRNA in a process called translocation, which requires the help of EF-2 (and GTP hydrolysis).  The first tRNA is moved into the exit site (E), and the second tRNA moves into the P site, while the A site is open for another aminoacyl-tRNA.

The process repeats until the ribosome encounters a stop codon.  At this point, termination factors (TFs), which have structures similar to tRNAs and bind mRNAs but do not have amino acids, enter the acceptor site of the ribosome.  The ribosome then catalyzes the addition of water to the end of the amino acid chain, releasing it from the peptidyl transferase center and allowing it to leave the ribosome and begin folding into its native conformation.

While there are several details that I may have seemingly glazed over, this post should give a broad, simplified overview of translation.  Future posts will address the many details involved.