Why is it that Glucose is the preferred (if not the only monosaccharide) that is ultimately used as the prime energy source? Why not galactose or fructose for example?
You are asking a "why" question. Such questions are easy to address but generally notoriously difficult to answer well. Let me make an attempt:
1) Since all carbohydrates share certain structural features in common they are likely to also share certain metabolic steps. Strings of such steps are usually referred to as metabolic pathways. These would generally be most employed for the energy extraction from the most readily available substrate. The metabolism of other similar substrates would employ some portions of the same pathways with the aid of specialized 'adapter' steps. Doing so conserves cellular resources.
2) Mammals generally store carbohydrate energy in the form of glycogen, and most tissues are generally primed to channel resources either for energy storage or energy utilization from stores, in response to hormonal signals. Most cells constitutively express receptors for glucose, and certain organs are almost wholly dependent on it for energy.
3) While other carbohydrate forms may also be used in most tissues, the necessary receptors are at least to some extent inducible. This helps conserve resources.
4) What the above reasoning leads us to is the following conclusion: A preferred substrate is employed in order to conserve resources. One could still argue: but why glucose? Would this kind of question be resolved if the preferred molecule was different?
You are asking a "why" question. Such questions are easy to address but generally notoriously difficult to answer well. Let me make an attempt:
1) Since all carbohydrates share certain structural features in common they are likely to also share certain metabolic steps. Strings of such steps are usually referred to as metabolic pathways. These would generally be most employed for the energy extraction from the most readily available substrate. The metabolism of other similar substrates would employ some portions of the same pathways with the aid of specialized 'adapter' steps. Doing so conserves cellular resources.
2) Mammals generally store carbohydrate energy in the form of glycogen, and most tissues are generally primed to channel resources either for energy storage or energy utilization from stores, in response to hormonal signals. Most cells constitutively express receptors for glucose, and certain organs are almost wholly dependent on it for energy.
3) While other carbohydrate forms may also be used in most tissues, the necessary receptors are at least to some extent inducible. This helps conserve resources.
4) What the above reasoning leads us to is the following conclusion: A preferred substrate is employed in order to conserve resources. One could still argue: but why glucose? Would this kind of question be resolved if the preferred molecule was different?
Danilo Boskovic, excellent answer........I guess I can add a little to that... Evolution might have played a role for the preference of glucose? When organisms were evolving glucose could have a been the prime source of carbohydrate.
But would you reckon the dextrose structure of glucose also plays a role; in which the dextrose structure favors crystallization to form Glycogen?
I agree with Sriharsha: I think Glucose was around when these relevant forms of metabolism evolved so we (and everything else) adapted to it. So today everything is perfect for glucose. I read an article about some experiments with bacteria a while ago, which where grown only with galactose. This lead to a quite fast mutation and adaptation in the enzymes which are important for galactose metablism, so my guess is that we could adapt for other sugars, but this would take quite a while.
I’ve always been a sucker for “why” questions, especially if they involve organic chemistry.
One interesting aspect of glucose is that it is among the few stable hexoses that can be formed abiotically. The stable glucose ring structure makes it less destructive for proteins, while still being calorie rich.
Bunn HF, Higgins PJ. Reaction of monosaccharides with proteins: possible evolutionary significance. Science. 1981 Jul 10;213(4504):222-4.
Why D-glucose was preferred over the L form is another interesting question. Some biochemistry could have originated on a solid surface.
Bondy SC, Harrington ME (1979) L-Amino acids and D-glucose bind stereospecifically to a colloidal clay. Science 203:1243–1244
Glucose metabolism (and glycogen storage) is a core gene pathway - its found in bacteria archaea and eukaryotes. So probably the most that we can readily say about question is that, first points out this pathway has proven to be useful at a critical juncture of the formulation of living things on earth. If you look at glucose metabolism pathways, you can see that glycerate compounds and pyruvate are the actual intermediates that are used to create energy. The first thing about these molecule worth noting is that they have a good mix of carbon and oxygen, which would make it easier to extract energy - creating CO2 from these compounds may even predates the existence of atmospheric oxygen. So glucose and fructose (which is actually derived from glucose in the metabolic pathway) are actually storage molecules themselves, easily broken down to smaller molecules.
There are quite a few ways to arrange oxygen around the carbohydrate ring. why glucose? The advantages of glucose is probably a subtle one. The structural properties of glycogen might be a reason that the use of glucose monomer is so important for glycogen. There is no evidence that I can find for this, so its always possible that glucose was just the first hexose carbohydrate to be biologically used. Its sort of hard to imagine that the structure of glucose does not play some sort of role in cell structure though.
Because there is no energy stored in oxygen, oxygen is the fire and hydrogen is the fuel... just a matter of who is who....
Carbohydrates are just a way nature captured and stored hydrogen for later use...
All carbohydrates are carriers of the "real fuel" and only element needed to create energy ... H .. number one on tabel of elements
there are three bio-molecules that can be utilized by the human being viz---carbohydrates,lipids and proteins .Out of these only carbohydrates especially glucose is most viable source because this is contained in all Veg. & non-veg foods and glycogen in liver and muscles can be stored .RBCs and brain require glucose as all enzymes required for catabolism i.e glycolysis and TCA are present in cytosol & mitochondria .This is true for all cells except RBCs which have no mitochondria.They depend on glucose only for survival. .Now fats in the form of fatty acids are used in the form of beta oxidation.This also requires mitochondria as it contains all enzymes for beta oxidation.But these have no utility for RBCs as mitochndria is again required for beta oxidation.Fats can account for 75% energy required for brain in the form of ketone bodies.If blood glucose falls further then hypoglycaemia does't allow RBCs and brain to procede further especially RBCs.IN this case amino acids help to allow gluconeogenesis so that blood glucose maintains at 70 to 80 mg.% . All this can not be explained in details in this small cutout,so I welcome all type of queries.
http://Intermediary metabolism available in all text books of medical biochemistry is helpful.As I have invited further details,I am here for facts.
Dr Danilo's answer is comprehensive and excellent. I only want to say that EVOLUTION is probably the answer to the questions he raised in point 4 of his fantastic contribution.
This is ridiculous to ignore the facts.We are in 21st century still exploring ancient times .All these are hard facts.I could sense uselessness of the very existence.
Answering a question starts with why is not trivial. The question could be philosophically (like why is it important) or how does it work or what or how insures that it works (mechanism).
As for the philosophy part of the question, the answer is: this is how our cells are built and this is our food. We eat mostly glucose as a mono or polysugar (starch). This is “Why not galactose or fructose”. In the other had our cells have the right enzymes to utilize glucose.
Mechanism: most of our cells express the enzymes enabling them to utilize glucose and other monosacchrides. Some others do not (like neorons) they use glucose. This is also why the liver produces glucose in the gluconeogenesis (synthesizing glucose from lactate or pyruvate) and glycogen degradation.
HOWEVER, not all animals prefer glucose. For instance immigrating birds or polar bears do store in their body fat (for long time) since fat is more efficient in energy compared with sugar (per weight) !!
Well! This question hints at two questions. The first is 'why carbohydrates are used to store energy?' in general and the second being 'why glucose rather than other carbohydrates?' in particular.
Glucose metabolism (and glycogen storage) is found in unicellular organisms. So probably this pathway has proven to be useful at some critical juncture of the formation of life on earth. If we look at glucose metabolism pathways, we find that glycerate compounds and pyruvate are the intermediates that are used to create energy. They have a good mix of carbon and oxygen, which would make it easier to extract energy - creating CO2 from these compounds may even predate the existence of atmospheric oxygen.
As to the second question: there are quite a few ways to arrange oxygen around the carbohydrate ring; then why glucose? The establishment of glucose as nutritional molecule is mainly linked with the availability of carbohydrates in the environment, i.e. plants as nutrition. Before plants evolved however, there were only bacteria and they use glucose as one of many oligosaccharides. But more important than glucose is trehalose because it is less toxic and can be collected in large amounts in the cell. The only reserves for glucose are glycogen and the bacterial cell wall which can be catabolized. So, the reason for the mere existence of glycolysis / gluconeogenesis pathways is the bacterial cell wall that has to be synthesized and catabolized. Only later were these pathways differentiated when land plants came up and animals that ate them.
Remember that land plants stem from green algae that were bacteria earlier. Green algae had not much of a glucose preference but they developed starch as an efficient reserve, in addition to glycogen and trehalose. Only when land plants needed thick cell walls and big structures, glucose needed to be produced en masse.
Let me answer this.. Why glucose? Right, in our body organs, any carbohydrate, lipid etc can use as energy source, but our brain is the most unique organ that can only use glucose as energy source
Great question and some really great answers here. I just have a few small points to make - not all cells prefer glucose. For instance work from Luc Pellerin and Piere Maggistretti have shown that neurons have an intrinsic preference for lactate (I guess lactate is mostly derived from glucose) as a fuel i.e. neuorns will preferentially utilise lactate over available glucose. I belive some immune cells (dont quote me on this though) preferentially utilise glutamine. And to touch on Nagarjuna Sivaraj's comment the brain can effectively utilise ketones when glucose is low during starvation.
We have to look at this question from a chemical point of view also because they are the laws that dictates our life. Like why is the water is the universal soluble? The same goes for glucose. So many factors are involved like the size of the molecule, its ability to create polymers, its ability to desolve and be desolved, it is ability to give negative and positive feedbacks. For instance, the BBB will show us why Glucose is extremely important as an energetic fuel for the brain. Due to its size, it can easily crosses the BBB. Due to its shape, it can easily be stored and reused when needed.
I have been following the contributions made by various esteemed researchers in answer to the question raised by Sriharsha. The question is such an interesting one. I however feel that chemistry alone may not provide us satisfactory answer. I don't think we can rule out the role of evolution. Because, in terms of energy content, is glucose different from its epimers such as galactose and mannose? They all have same molecular formula. If the three are passed through combustion, will they not give same calorie of energy? Also in terms of size, do these three compounds differ? Yes, in terms of isomerism they are not the same. Agreed. But the fundamental question raised by Sriharsha is WHY GLUCOSE IS THE PREFERRED ENERGY SOURCE. In other words, why does the living system single out glucose and not any of the other isomers of glucose that could have also yielded same energy content? Let me extend Sriharsha's question further with another question. WHY DOES THE BODY PREFER D-GLUCOSE TO L-GLUCOSE? I believe that Sriharsha's question will be satisfactorily answered if we can answer why the body prefers D-glucose. Same as why the body prefer L-amino acids rather than D-amino acids. I sincerely think that this question has evolutionary and philosophical dimensions. It seems to go a little beyond the confines or domain of chemistry. My opinion is that the answer we are seeking lies in the contributions of Danilo, Hilal and Alejandro. I sincerely appreciate everyone who has given an answer to this question. I find this contribution very stimulating and interesting indeed! Thank you Sriharsha for posing such a very interesting and challenging question
Regarding you question, it is important to note the following facts:
1- Glycolysis is the primary pathway that starts with metabolic activity of one of the two enzymes i.e. HEXOKINASE (in all tissues) and GLUCOKINASE (in liver). Hexokinase has relative specificity, it can utilises other hexoses also (so glucose is not the only source), while glucokinase has absolute specificity, it phosphorylates only glucose.
2- The two important polysaccharides utilized or stored by the organisms are STARCH & GLYCOGEN, which are polymer of GLUCOSE.
3- GLUCOSE is the most abundant monosaccharide.
All of these facts are showing that there is some genetic basis and the abundance of glucose, which make it preferable over other monosaccharides.
Both fructose and galactose are also used as sources of energy and enter short pathways which connect to glycolysis. The selection of glucose as the primary metabolic fuel may stem from the fact that it exists almost excusively in the pyranose form where all substituents (apart from the anomeric hydroxyl) are equatorial. Other sugars (eg. fructose) have non-negligible proportions of furanose isomers which could not be acted upon by catabolic enzymes which presumably evolved to specifically act on six-membered substrates, thus reducing the 'fuel efficiency'.
Because its the simplest compound... And remember the universal biological process of glycolysis.
As u must be aware of the structure of formaldehyde (HCHO) , this was formed during prebiotic condition , glucose also has got same strucure , it falls under aldohexose sugar category . Therefore it is formed from formaldehyde . It has very low tendency to glycosylate proteins non-enzymatically. Proteins once they are glycosylated they lose their vital function. It is the only fuel brain uses during non-starvation condition. Only fuel the red blood cell can use at all.
Dear Sriharsha,
Indeed, a very interesting question. I really complement Danilo, David, Stephen, and Olorunfemi for excellent contributions.
I also feel that Dobzhansky's answer is a key: "Nothing in Biology Makes Sense Except in the Light of Evolution".
I read the entire discussion and concluded that it may benefit from another point of view, which I feel was seriously overlooked. Life could not possibly emerged from oxygenated atmosphere and premanufactured glucose. If life started, as I believe, from anareobic conditions and simple energy sources (chemical or thermal or electromagnetic - light), then sugars are the products not the substrates and then gluconeogenesis was invented before glycolysis. Sugars must have been useful storage devices with a relative ease to retrieve the energy. Many methanogens or CO2 bacteria and archeons can also utilize sugars.
So, the minimal conditions were: easy to manufacture, relatively stable and easy to utilize. So speculating even further, all kinds of sugars were initially attempted to be this golden standard by our progenitors (archaic bacteria), and this is probably why our biochemistry utilizes all simple compounds with less than 6 carbons so abundantly (vide Krebs cycle). Glucose passes this golden standard: 1) relatively stable in pyranose form, six carbon provides a sufficient separation for the electrostatic centers (in form of phosphates) to provide catalytic suitable handle, and reducing it by half introduces it to the minimal biochemistry units suitable for further processing with both halfs, additionally from synthetic point of view a similar chirality of every carbon provides additional simplicity.
Therefore, without criticizing, I think that glucose as a food source is secondary. We all adapted to the initial store of sugars produced by our ancestors and our secondary biochemistry (organs and tissues) taken advantage of the existing, but where not primary reasons for it.
Glucose is the substrate used in pentose phosphate pathway where the building materials for nucleic acids and nucleotide (ribose-phosphate) and reducing equivalent (NADPH) are produced. As noted already by others, glucose is also the obligate substrate for red cells and brain. These reasons probably suggest that glucose is a substrate that is required for basic maintenance of life. Glucose can be metabolized to produce energy under anaerobic condition via glycolysis in cytosol whereas some others (e.g. fat) require oxygen and must be in mitochondria. So glucose perhaps also support survival in harsh conditions. All these likely played roles during evolution making it the preferred energy source. However, the question why the D-form is preferred to L-form and the other way around for amino acids and lactate is not understood. Someone touched this but now it is not seen here any more. Steingrimur thank you very much for the lead but I could not find the topic at Olorunfemi's site.
@ZengKui. There is a thread started by Olorunfemi Eseyin discussing the origins of stereoisomers in biology.
I actually disagree with the premise in the original question. If it is glucose the primary energy substrate we wouldn't store so little of it (the amount stored as glycogen is estimated at less than 400gm - not enough to support a full day of fasting). The primary energy source should be fat which we save a copious amount of. My research of existing papers leads me to conclude that fatty acid is overwhelmingly the preferred substrate for mitochondria.
Samples:
PMID: 17008367 Quote: "In aerobic heart, the preferred substrates are always free fatty acids."
Glucose may be the obligate substrate for RBC (and sperm) but not the brain which switches to ketone when glucose supply is low.
PMID: 21165293. Title: "Ketonuria after fasting may be related to the metabolic superiority"
I agree that fatty acids are the basic substrates for the citiric acid cycle. In fact, ruminant animals are ketogeic in their metabolism, the bacteria actualy convert cellulose to fatty acids for absorption and metabolism. Phenomenal brain growth in mammals necessitated large amounts of fatty acids for metbolism which essentially altered our pH homeostasis, when nature re introduced glucose as the source, which can be generated by gluconeognesis at the liver and a wide range of blood levels is possible with little acidotic or osmotic challenge. Nature it realy brilliant. In fact I had read a review article highlighting these facts and I am sorry that I am unable to locate and attach the same.
Because presence of glucose blocks pathways of other objects via cAMP mediated negative regulation. So even if other sugars and fatty acids are present, glucose will be metabolised first.
There are some good answers here, but I would expound upon them from an evolutionary perspective. The structural equilibrium of glucose favors the ring form over the linear form 99.7% of the time. That is to say that 0.3% or less of blood glucose is in the open, linear form at any given time. This is significant as it is the linear form that is capable of glycating body proteins (leading to an increase in HbA1c for example). All other aldohexoses have a larger proportion in the linear form and would lead to more protein glycation than glucose. As we learn more about the pathologies associated with advanced glycation end products in the sequalae of diabetes, it becomes clearer that keeping glycation to a minimum is a survival advantage.
You are right to say that fats or lipids are more energy -dense and stored in higher amounts in the body. But the question is WHY IS IT THE PREFERRED? In addition to the reasons given by colleagues above,I think that unlike fats(fatty acids), glucose is used by all cells in the body., in fact, red blood cells and brain cells utilize only glucose to generate energy. Catabolism of fats produces ketone bodies which can be detrimental to the body. Glycogen is stored in large amounts in the liver and muscle. One glycogen molecule can release hundreds of glucose molecules in the process of glycogenolysis, transport system for glucose across the membrane is simple and efficient.
Sorry Jana Simmons - I believe that is wrong assumption - the equilibrium means that 99,7% of the glucose is available to be transformed to the open state all the time, so once 0,3% is conjugated, another portion (it's not portion, but a linear transformation, I have used "portion" for clarity) is transformed from hexopyranose form to the linear one. The overall reaction rate is the rate of 2 equilibria, not just one.
Another thing - the answer to "why glucose" is rather simple. Glucose is all-equatorial -OH, which renders the hexopyranose form the most stable among the sugars. Accordingly, it is the most abundant sugar in the nature (just immagine - all cellulose, starch,...), so all the organisms adapted to the most abundand sugar and not the other way around.
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