Structural Biochemistry/Proteins/Amino Acid Biosynthesis

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Overview

To synthesize amino acids, there must be a source of nitrogen that is in a form that can be easily used. Various microorganisms reduce inert nitrogen gas into two molecules of ammonia to provide for this source of nitrogen. On the other hand, the carbon backbone can be provided in three different ways--these include the citric acid cycle, the glycolytic pathway, and the pentose phosphate pathway.


Since amino acids are all chiral except for glyciene, biosynthesis of amino acides must generate the correct isomers efficiently. This is done by transamination reactions and high regulation of biosynthetic pathways, through feedback and other mechanisms.



Nitrogen Fixation

To reduce atmospheric nitrogen gas (N2) to ammonia (NH3, a process called nitrogen fixation, microorganisms require ATP. Nitrogen fixation is performed by nitrogenase complex, an enzyme that has many centers for redox. This enzyme is composed of a reductase and nitrogenase. The reductase provide electrons while the nitrogenase uses these electrons, reducing atmospheric nitrogen to ammonia in the following reaction:



N2 +8 e- + 8 H+ <--> 2 NH3 + H2



Most microorganisms that are capable of nitrogen fixation carry out this reaction by generating a reduced ferredoxin through photosynthesis, providng the electrons. Two molecules of ATP are then used to transfer each electron, meaning that 2x8=16 electrons are needed to generate the two molecules of ammonia. The total reaction for this can then be written as:
N2 +8 e- + 8 H+ + 16 ATP + 16 H2O <--> 2 NH3 + H2 + 16 ADP + 16 Pi
Then, through the amino acids glutamine and glutamate, ammonium ion (NH4+)is assimilated.



Chirality

Of the 20 amino acids, humans can synthesize 11 of them. These amino acids are referred to as nonessential amino acids. The remaining 9 amino acids are referred to as essential amino acids, and they must be provided for in the diet. Synthesizing the 11 nonessential amino acids require different intermediates, but one fact remains common among them--the gycolytic pathway, the citric acid cycle, and the pentose phosphate pathway provide intermediates that their carbon skeletons come from. Also, in all these amino acids, the same step ensures the correct chirality. This step is in a transamination reaction, and a quinonoid intermediate is protonated, forming an external aldimine. The direction the proton comes from dictates the amino acid's chirality.



Regulation by Feedback

The rate of amino acid biosynthesis depends on the amount of enzymes present and the activity of those enzymes. However, there are other ways of regulating the biosynthesis of amino acids.



Feedback Inhibition

The first reaction that is irreversible in the biosynthesis of amino acids is referred to as the committed step, and the feedback loop of amino acid synthesis is a negative one, with the product inhibiting the catalyst to the committed step. This indicates that the biosynthesis of amino acids is regulated by a negative feedback loop. There are variety of different feedbacks that regulate the synthetic pathway.



Branched Pathways

Branched pathways are more complex in that they involve more sophisticated regulation. They can involve both positive and negative feedback. In other words, reactions have both feedback inhibition and feedback activation. An example of this is the enzyme threonine deaminase. This enzyme converts threonine to alpha-ketobutyrate, and valine activates this process, while isoleucine inhibits it.


Branched pathways may also involve enzyme multiplicity, a phenomenon in which multiple enzymes regulate or catalyze one single reaction. These enzymes may all have different activities and different regulatory mechanisms. Lastly, in cumulative inhibition, multiple proteins are capable of inhibiting one enzyme's activity. Even if the inhibited enzyme is saturated with one protein, other inhibiting proteins can still continue to reduce its activity. An example of this is the cumulative feedback inhibition of glutamine synthetase in E. coli.


Enzymatic cascade is another form of regulation in branched pathways. An enzymatic cascade is a reaction that requires successive steps of enzymatic catalysis after initiation. The advantages of this process is that it can amplify signals and highly increase allosteric control. This is due tot he fact that requiring different enzymes basically combines multiple regulations of the enzymes, so that the process, in entirety, will have all these regulations occurring. This extends the potential for more efficient accruing of nitrogen in the cell.



So What?

Why is the biosynthesis of amino acids important? Amino acids are not only the basic building blocks to all peptides and proteins. A wide variety of biomolecules are also derived from amino acids. Examples of these include the purine and pyrimidine bases in DNA and RNA, a vasodilating protein called histamine, the hormone thyroxine, and the hormone epinephrine, to name a few. Amino acids are also a part of other compounds in the body, such as buffers, antioxidants, and enzymes. Another molecule formed from amino acids is nitric oxide (NO). Nitric oxide is derived from arginine, and serves as a messenger in signal transudction.


As amino acids are involved in the synthesis of so many proteins and compounds within the body, lack of amino acids therefore has its consequences. Various inherited disorders may occur as a result of lack of a certain amino acid, or a certain compound derived from amino acids. An example is porphyrias. Thisdisorder may be inherited or acquired during one's lifetime, and it is due to a deficiency of heme pathway enzymes.







Source: Berg, Jeremy and Stryer, Lubert. Biochemistry: Fifth Edition. United States of America: W.H. Freeman and Company, 2002.