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Wednesday, April 29, 2009

Head Growth and Tail Growth

There are many examples of polymerization reactions in biochemistry: DNA/RNA synthesis, protein synthesis, carbohydrate synthesis and fatty acid synthesis. In some cases the polymer consists of a string of identical monomers (e.g. some carbohydrates, fatty acids) while in other cases the polymer can be a mixture of several different kinds of monomers (e.g. nucleic acids, proteins).

There are two basic strategies of polymerization: head growth and tail growth. The basic concept is often presented in the textbooks when DNA synthesis or protein synthesis is described.

I posed a simple question yesterday and got some comments on the blog and in my email [Are You as Smart as a Second Year University Student? Q6]. Some people didn't have a clue what the question was about and some people declared that the question was silly. One commenter said, "Sounds like a stupid question that has something to do with memorizing someone's silliness and nothing to do with understanding biochemistry."

Let's see if you agree that this is a silly question that has nothing to do with understanding biochemistry.

In head growth the head of the growing polymer is "activated"—it carries the energy for the addition of the next monomer. This "activation" energy is depicted below as a red bond. Each of the incoming monomers is also "activated" but the energy of the activated bond will be used for the next addition once the monomer is added to the growing polymer.

The classic example of head growth is protein synthesis. Fatty acids are also made in this way.

In tail growth the head of the growing polymer is not activated. The energy for the addition of each monomer is supplied by the incoming activated monomer.

The best examples of tail growth strategy are nucleic acid synthesis, where the activated monomers are nucleoside triphosphates, and synthesis of storage polysaccharides, where the activated monomer is UDP-glucose.

Why is it important to understand the difference between head growth and tail growth? Because one type is unidirectional whereas the other type is compatible with both lengthening and shortening of the polymer.

Let's look at the process of error correction as seen in the proofreading reaction of DNA biosynthesis. Imagine that the replication complex makes a mistake and adds the wrong nucleotide to the growing DNA molecule. The incorrect nucleotide is subsequently removed by the proofreading activity of DNA polymerase. Since DNA synthesis is a tail growth mechanism, the removal of the most recently added monomer doesn't change the chemical reactivity of the growing end of the chain so the reaction can now continue in the direction of lengthening as shown by the green check mark in the figure.

If DNA synthesis utilized a head growth mechanism, then proofreading would not have evolved since removal of the last monomer also removes the activated head of the growing chain.1 That's why there's no proofreading in protein synthesis.

The synthesis of storage carbohydrates such as starch and glycogen doesn't involve proofreading but there's still a very good reason why the mechanism is tail growth. Recall that starch and glycogen are polymers of glucose and their role is to store glucose as a potential carbon source in time of need. When the need arises, the ends of the polysaccharide chains are nibbled back releasing glucose molecules (as glucose-6-phosphate). These molecules enter the glycolysis pathway.

The degradation reaction terminates when the immediate need for glucose has been met. Later on, in time of plenty, the starch and glycogen chains can be re-extended by adding more glucose residues. The reason why this is possible is because starch and glycogen synthesis is an example of tail growth just like nucleic acid synthesis. If nibbling the ends of the polysaccaride chains removed the activated head, as it would in the case of head growth, then the synthesis reaction could not occur. Thus, the fundamental reason why tail growth evolved in both nucleic acid synthesis and glycogen synthesis is the same.

One of the other reasons for discussing this concept in introductory biochemistry classes is that it gets students thinking about the big picture. Rather than focusing on the details of any one type of polymerization reaction they are encouraged to think about general strategies and they are stimulated to compare and contrast different types of reactions. Unfortunately this approach is rapidly disappearing from introductory biochemistry courses because they are often taught in sections where the lecturer in each section is a specialist in information flow, carbohydrate metabolism, or protein structure. These lecturers often don't know enough about the other subjects to make the relevant comparisons.

That wouldn't matter a great deal as long as the introductory biochemistry textbooks did the job for them. There are two reasons why that doesn't seem to work. First, many team-taught courses don't use a textbook because the individual experts in each section think they know everything they need to know and the students can just rely on the lecture notes.

Second, the comparative biochemistry concepts and principles are disappearing from the textbooks. This is partly because of the way courses are taught and the way students are examined—once the exam on carbohydrate metabolism is over, students don't have to remember anything about carbohydrates while preparing for the next test on lipids and membranes. It's also partly because some biochemistry courses don't cover all aspects of biochemistry in a single course. Many introductory biochemistry courses, for example, separate information flow (DNA replication, transcription, translation) from the rest of biochemistry.

Because of the negative feedback from the customers (Professors) my textbook does not mention head growth and tail growth. The concept is also missing in all of the other introductory biochemistry textbooks.

I'm putting it back in the next edition of my book even if it means losing some adoptions.

1. Admittedly, one could imagine evolving ways around this limitation; by re-activating the end in a separate reaction, for example.


paul01 said...

As a possessor of a degree in History, I found that fascinating. (I have often been puzzled by "proofreading").

Thanks for this, and your many other posts on such matters.

DK said...

I feel that this is straight out of some adaptationist bible. I.e. "if it exists, it must be super-important for [insert post hoc explanation]".

As you mention yourself, there is basically nothing wrong with reactivating the end if the need be and continue to go with the synthesis/proofreading activity. Certainly there are much more arcane ways of accomplishing things in the cell.

Moreover, DNA proofreading almost certainly evolved long time after the basic chemistry was set up in stone (i.e., RNA world; RNA, I'd surmise, is made the same 5'->3' way). This kind of leaves the whole head/tail thing and its improtance pretty moot.

Finally, it is not too difficult to come up with a mechanism that would enable proofreading in translation. But evidently that did not happen - whih may, in fact, be a pure chance event.

Anonymous said...

There needs to be a better term than "head" and "tail" since it is not obvious that "head" does or does not contain energy and similarly for "tail".

Maybe something like "polymer activated" or "monomer activated" to describe whether the energy driving polymerization is contained in the polymer or in the monomer.

The Lorax said...


There is proofreading in translation, a fair bit actually. Its just not like DNA. But so what, who ever said DNA proofreading is the right way?

DK said...

@ The Lorax:

There is proofreading in translation, a fair bit actually.

Larry disagrees:
[protein synthesis is a "head growth"] and "that's why there's no proofreading in protein synthesis".

I tend to agree with Larry. The well-known kinetic proofreading is actually a misnomer because it's a quality control that ensures proper synthesis but does not *correct* mistakes in polymerization that have been made. Unless you are saying that there does exist a real proofreading in translation, with nimbling down and restarting (?). I am not aware of such (if that were to happen, won't the polypepthe chain fall off the ribosome and be lost?).

To add my to my previous comment: isn't the basic polymerization chemistry is the same for all complex carbohydrates (say, chitin or agarose)? If so, it seems highly dubious to assign "the fundamental reason why tail growth evolved [emphasis mine - DK] in both nucleic acid synthesis and glycogen synthesis".

Anonymous said...

lol wut shit has everything to do with biochemistry

The Lorax said...


I didn't say translation proofreading occurred in the same way it does for replication. As you noted it does occur, but you dont except it and want to redefine decades old terminology to suit your perspective.

I can level the same "redefining terms" accusation at Larry, but from his context I assumed he was specifically talking about an C-terminal to N-terminal exopeptidase activity analogous to DNA replication. Based on the "tail growth" model, it seems like proofreading must occur before synthesis (just like in translation).

I am interested in your easily envisioned evolution of a mechanism for proofreading in translation similar to replication.

DK said...

@ Lorax:
I am interested in your easily envisioned evolution of a mechanism for proofreading in translation similar to replication.Well, I did not say "evolution". I just said alternatives are possible. Here is the first fantasy that comes to mind (there ought to be 100s more possible):

Redundancy. Right after peptide bond formation and before translocation, check once again that the codon matches. If not, full stop, no translocation. The stalled state is subject to the competing peptidase and non-specific aminoacyl transferase activities - until the second check gives green light and translocation occurs.

Anonymous said...

When does the next edition of the textbook come out?

Larry Moran said...

When does the next edition of the textbook come out?

Hopefully in January 2011.

Unknown said...

Such an interesting concept; something that I'd never heard of in my past four years as a molecular genetics undergrad at UofT, and especially while taking BCH242; primarily I presume, because of the way the course was taught (as you mentioned, complete separation of all the four sections from one another) as well as the supposed fear of the instructors that if they bring up anything remotely related to organic chemistry, it's going to offense the students (which brings up the question of "why do you guys then make the poor students suffer through two organic chemistry courses if they're not supposed to see their application in biochemistry and molecular biology?!"). I'm curious to read a more in detail your explanation of the two mechanisms, is your book out for us, the class of '20 people, yet?!