Science: Metabolic Poisons, Introduction

All living beings need to breathe, drink and eat to survive. Staying alive requires chemical processes to break down complex molecules to obtain energy, and reassemble simple molecules in the body for growth and reproduction. This is metabolism, and today we are going to explore three deadly plant toxins that end the processes of life. The super star poison cyanide, rotenone and carboxyatractyloside, here we go!

 

Before I start let me give you a crash course on cellular respiration. After all, the rule of three posits that we can only survive three weeks without food, three days without water, and 3 minutes without oxygen. Food, water and oxygen play a key role in metabolism because our body uses them to make energy. Energy does work, from beating of a heart, to thinking processes, to movement, digestion and excretion. Many organs and cells of our body, in particular those with high energy demand such as the heart, brain and muscle keep an energy power-house or generator called mitochondrion (plural mitochondria). In fact, mitochondrion could be one of the oldest friends made by our earliest single cell ancestors. It is a tiny cell living inside ours cells, helping us to produce energy while gaining our protection. Each mitochondrion has its own membrane and even remnant DNA, it is a chemical  factory that produces the vital molecule ATP (adenosine triphosphate). ATP stores energy in its phosphate chemical bond and whenever energy is required, ATP is broken down into ADP (adenosine diphosphate), releasing energy and a phosphate group. Most importantly, ADP can be recharged like a battery into ATP to be reused. To understand our metabolic poisons is to understand how mitochondria produces and recycles ATP. 

 

Figure 1: Overview of cellular respiration.

Examine Figure 1 carefully. Our body has three principal ways of making ATP, namely, glycolysis, Kreb’s cycle, and electron transport chain. The first method, glycolysis takes place outside of mitochondria (in cytoplasm of a cell). Glycolysis makes ATP from carbohydrates (sugar, glucose) that we consume, releasing carbon dioxide as a by-product. It also generates a reactive molecule called pyruvate (transformed into acetyl-CoA), and taken up by mitochondria to participate in the Kreb’s cycle. In the Kreb’s cycle, various oxidation-reduction steps occur, and ATP is generated alongside two important molecules called NaDH (nicotinamide adenine dinucleotide) and FaDH₂ (Dihydroflavine dinucleotide), both containing extra electrons as reducing agents. Hence NaDH and FaDH₂ can give away two electrons and hydrogen atoms, and become themselves oxidised. It is the NaDH and FaDH₂ that will eventually take part in the last ATP making process, the electron transport chain (ETC). 

 

Figure 2: Simplified diagram of the electron transport chain.

The ETC is like a hydroelectric power generator. It accumulates potential energy in the form of hydrogen ions (protons) at two sides of the mitochondria membrane, much like water is contained in a dam up a mountain. It is the potential energy of protons that ETC harvests to produce a lot of ATP. It does so by transporting electrons across the inner membrane to induce hydrogen ions to accumulate on the outer membrane side (Figure 2). After all, electrons are negatively charged and hydrogen ions are positive. The ETC comprises of four complexes, namely complex I, II, III, and IV, which facilitate electron transport. These are called complexes because they are indeed complex proteins incorporated with enzymes. Except for complex II, all other complexes will move a proton from inner to outer mitochondria membrane whenever they receive an electron. Complex I receives its electron and proton from NaDH, while complex II from FaDH₂. Complex I and II then hire a middleman called ubiquinone (co-enzyme Q10) to pass their electrons to complex III, which functions mainly to transfer protons to the outer membrane and regenerating ubiquinone in the process. Complex III contains a protein called cytochrome c, which is incorporated with a heme group containing iron. It is much like the haemoglobin protein in our blood. The iron atom in the heme transports electrons one at a time between the oxidation states of Fe²⁺ (gained 1e^-) and Fe³⁺ (lost 1e^-). Lastly, complex III transfers its electron to cytochrome c proteins (another middleman), and finally to complex IV (cytochrome c oxidoreductase), which is the receiving end of  ETC. The free electrons are given to an oxygen atom in a reduction step to produce water. That is why we breathe, we give electrons to oxygen to make water and ATP in the ETC! Complex IV also contains a heme protein, together with a copper ion to grab hold of an oxygen atom while it is being force-fed with electron. Now having rid the electrons, ETC has accumulated lots of proton potential energy (called proton gradient), which is harvested by the ATP-making enzyme ATP-synthetase. ATP synthetase allows protons to flow in from the outer membrane, creating a ‘torrent’ that is used to power the recharge of ADP into ATP. Of course, to facilitate the transport of ADP and ATP in and out of the mitochondria membrane, a transport protein called ADP-ATP translocase is utilised. All these proteins and complexes work together day and night to power our survival. In terms of the amount of ATP that is produced, ETC accounts for 8 times more output than glycolysis and Kreb’s cycle combined!

 

That's it for today because I guess this is quite a bit for those of you who do not have a biochemistry background.  I hope you are still with me. Again, I emphasise that it is only when we understand these basics of life processes that we can understand how metabolic poisons work. Have fun reading and next time, we will look at a plant toxin that targets complex I of the ETC.