The Cori Cycle

Animals can synthesize glucose 6-phosphate via gluconeogenesis just like all other species. However, unlike most species, animals can convert glucose 6-phosphate to glucose, which is secreted into the circulatory system. Mammals, in particular, have a sophisticated cycle of secretion and uptake of glucose. It's called the Cori cycle after the Nobel Laureates: Carl Ferdinand Cori and Gerty Theresa Cori.


The glucose 6-phosphate molecules synthesized in the liver can either be converted to glycogen [Glycogen Synthesis] or converted to glucose and secreted into the blood stream. The glucose molecules are taken up by muscle cells where they can be stored as glucogen. During strenuous exercise the glycogen is broken down to glucose 6-phosphate [Glycogen Degradation] and oxdized via the glycolysis pathway. This pathway yields ATP that is used in muscle contraction.

If oxygen is limiting, the end product of glucose breakdown isn't CO₂ but lactate. Lactate is secreted into the blood stream where it is taken up by the liver and converted to pyruvate by the enzyme lactate dehydrogenase. Pyruvate is the substrate for gluconeogenesis. The synthesis of glucose in the liver requires energy in the form of ATP and this energy is supplied by a variety of sources. The breakdown of fatty acids is the source shown in the figure.

The Cori cycle preserves carbon atoms. The six carbon molecule, glucose, is split into two 3-carbon molecules (lactate) that are then converted to another 3-carbon molecule (pyruvate). Two pyruvates are joined to make glucose.

Adaptation and Accident in PNAS

 
This week's issue of the Proceedings of the National Academy of Sciences (USA) (PNAS) has a number of articles on evolution. The most interesting to me are the ones that debate the role of natural selection. I haven't had time to read them yet but here's a heads up.

Michael Lynch, The frailty of adaptive hypotheses for the origins of organismal complexity.

The vast majority of biologists engaged in evolutionary studies interpret virtually every aspect of biodiversity in adaptive terms. This narrow view of evolution has become untenable in light of recent observations from genomic sequencing and population-genetic theory. Numerous aspects of genomic architecture, gene structure, and developmental pathways are difficult to explain without invoking the nonadaptive forces of genetic drift and mutation. In addition, emergent biological features such as complexity, modularity, and evolvability, all of which are current targets of considerable speculation, may be nothing more than indirect by-products of processes operating at lower levels of organization. These issues are examined in the context of the view that the origins of many aspects of biological diversity, from gene-structural embellishments to novelties at the phenotypic level, have roots in nonadaptive processes, with the population-genetic environment imposing strong directionality on the paths that are open to evolutionary exploitation.

Francisco J. Ayala, Darwin's greatest discovery: Design without designer.

Darwin's greatest contribution to science is that he completed the Copernican Revolution by drawing out for biology the notion of nature as a system of matter in motion governed by natural laws. With Darwin's discovery of natural selection, the origin and adaptations of organisms were brought into the realm of science. The adaptive features of organisms could now be explained, like the phenomena of the inanimate world, as the result of natural processes, without recourse to an Intelligent Designer. The Copernican and the Darwinian Revolutions may be seen as the two stages of the one Scientific Revolution. They jointly ushered in the beginning of science in the modern sense of the word: explanation through natural laws. Darwin's theory of natural selection accounts for the "design" of organisms, and for their wondrous diversity, as the result of natural processes, the gradual accumulation of spontaneously arisen variations (mutations) sorted out by natural selection. Which characteristics will be selected depends on which variations happen to be present at a given time in a given place. This in turn depends on the random process of mutation as well as on the previous history of the organisms. Mutation and selection have jointly driven the marvelous process that, starting from microscopic organisms, has yielded orchids, birds, and humans. The theory of evolution conveys chance and necessity, randomness and determinism, jointly enmeshed in the stuff of life. This was Darwin's fundamental discovery, that there is a process that is creative, although not conscious.

Cynthia M. Beall, Two routes to functional adaptation: Tibetan and Andean high-altitude natives.

Populations native to the Tibetan and Andean Plateaus are descended from colonizers who arrived perhaps 25,000 and 11,000 years ago, respectively. Both have been exposed to the opportunity for natural selection for traits that offset the unavoidable environmental stress of severe lifelong high-altitude hypoxia. This paper presents evidence that Tibetan and Andean high-altitude natives have adapted differently, as indicated by large quantitative differences in numerous physiological traits comprising the oxygen delivery process. These findings suggest the hypothesis that evolutionary processes have tinkered differently on the two founding populations and their descendents, with the result that the two followed different routes to the same functional outcome of successful oxygen delivery, long-term persistence and high function. Assessed on the basis of basal and maximal oxygen consumption, both populations avail themselves of essentially the full range of oxygen-using metabolism as populations at sea level, in contrast with the curtailed range available to visitors at high altitudes. Efforts to identify the genetic bases of these traits have included quantitative genetics, genetic admixture, and candidate gene approaches. These reveal generally more genetic variance in the Tibetan population and more potential for natural selection. There is evidence that natural selection is ongoing in the Tibetan population, where women estimated to have genotypes for high oxygen saturation of hemoglobin (and less physiological stress) have higher offspring survival. Identifying the genetic bases of these traits is crucial to discovering the steps along the Tibetan and Andean routes to functional adaptation.

Adam S. Wilkins, Between "design" and "bricolage": Genetic networks, levels of selection, and adaptive evolution.

The extent to which "developmental constraints" in complex organisms restrict evolutionary directions remains contentious. Yet, other forms of internal constraint, which have received less attention, may also exist. It will be argued here that a set of partial constraints below the level of phenotypes, those involving genes and molecules, influences and channels the set of possible evolutionary trajectories. At the top-most organizational level there are the genetic network modules, whose operations directly underlie complex morphological traits. The properties of these network modules, however, have themselves been set by the evolutionary history of the component genes and their interactions. Characterization of the components, structures, and operational dynamics of specific genetic networks should lead to a better understanding not only of the morphological traits they underlie but of the biases that influence the directions of evolutionary change. Furthermore, such knowledge may permit assessment of the relative degrees of probability of short evolutionary trajectories, those on the microevolutionary scale. In effect, a "network perspective" may help transform evolutionary biology into a scientific enterprise with greater predictive capability than it has hitherto possessed.

John Gerhart and Marc Kirschner, The theory of facilitated variation

This theory concerns the means by which animals generate phenotypic variation from genetic change. Most anatomical and physiological traits that have evolved since the Cambrian are, we propose, the result of regulatory changes in the usage of various members of a large set of conserved core components that function in development and physiology. Genetic change of the DNA sequences for regulatory elements of DNA, RNAs, and proteins leads to heritable regulatory change, which specifies new combinations of core components, operating in new amounts and states at new times and places in the animal. These new configurations of components comprise new traits. The number and kinds of regulatory changes needed for viable phenotypic variation are determined by the properties of the developmental and physiological processes in which core components serve, in particular by the processes' modularity, robustness, adaptability, capacity to engage in weak regulatory linkage, and exploratory behavior. These properties reduce the number of regulatory changes needed to generate viable selectable phenotypic variation, increase the variety of regulatory targets, reduce the lethality of genetic change, and increase the amount of genetic variation retained by a population. By such reductions and increases, the conserved core processes facilitate the generation of phenotypic variation, which selection thereafter converts to evolutionary and genetic change in the population. Thus, we call it a theory of facilitated phenotypic variation.

Benjamin Prud'homme, Nicolas Gompel, and Sean B. Carroll, Emerging principles of regulatory evolution

Understanding the genetic and molecular mechanisms governing the evolution of morphology is a major challenge in biology. Because most animals share a conserved repertoire of body-building and -patterning genes, morphological diversity appears to evolve primarily through changes in the deployment of these genes during development. The complex expression patterns of developmentally regulated genes are typically controlled by numerous independent cis-regulatory elements (CREs). It has been proposed that morphological evolution relies predominantly on changes in the architecture of gene regulatory networks and in particular on functional changes within CREs. Here, we discuss recent experimental studies that support this hypothesis and reveal some unanticipated features of how regulatory evolution occurs. From this growing body of evidence, we identify three key operating principles underlying regulatory evolution, that is, how regulatory evolution: (i) uses available genetic components in the form of preexisting and active transcription factors and CREs to generate novelty; (ii) minimizes the penalty to overall fitness by introducing discrete changes in gene expression; and (iii) allows interactions to arise among any transcription factor and downstream CRE. These principles endow regulatory evolution with a vast creative potential that accounts for both relatively modest morphological differences among closely related species and more profound anatomical divergences among groups at higher taxonomical levels.

Nancy A. Moran, Symbiosis as an adaptive process and source of phenotypic complexity.

Genomics has revealed that inheritance systems of separate species are often not well segregated: genes and capabilities that evolve in one lineage are often stably acquired by another lineage. Although direct gene transfer between species has occurred at some level in all major groups, it appears to be far more frequent in prokaryotes than in multicellular eukaryotes. An alternative to incorporating novel genes into a recipient genome is acquiring a stable, possibly heritable, symbiotic association and thus enjoying benefits of complementary metabolic capabilities. These kinds of symbioses have arisen frequently in animals; for example, many insect groups have diversified on the basis of symbiotic associations acquired early in their evolutionary histories. The resulting associations are highly complex, often involving specialized cell types and organs, developmental mechanisms that ensure transfer of symbionts between generations, and mechanisms for controlling symbiont proliferation and location. The genomes of long-term obligate symbionts often undergo irreversible gene loss and deterioration even as hosts evolve dependence on them. In some cases, animal genomes may have acquired genes from symbionts, mirroring the gene uptake from mitochondrial and plastid genomes. Multiple symbionts often coexist in the same host, resulting in coadaptation among several phylogenetically distant genomes.

Giorgio Bernardi, The neoselectionist theory of genome evolution.

The vertebrate genome is a mosaic of GC-poor and GC-rich isochores, megabase-sized DNA regions of fairly homogeneous base composition that differ in relative amount, gene density, gene expression, replication timing, and recombination frequency. At the emergence of warm-blooded vertebrates, the gene-rich, moderately GC-rich isochores of the cold-blooded ancestors underwent a GC increase. This increase was similar in mammals and birds and was maintained during the evolution of mammalian and avian orders. Neither the GC increase nor its conservation can be accounted for by the random fixation of neutral or nearly neutral single-nucleotide changes (i.e., the vast majority of nucleotide substitutions) or by a biased gene conversion process occurring at random genome locations. Both phenomena can be explained, however, by the neoselectionist theory of genome evolution that is presented here. This theory fully accepts Ohta's nearly neutral view of point mutations but proposes in addition (i) that the AT-biased mutational input present in vertebrates pushes some DNA regions below a certain GC threshold; (ii) that these lower GC levels cause regional changes in chromatin structure that lead to deleterious effects on replication and transcription; and (iii) that the carriers of these changes undergo negative (purifying) selection, the final result being a compositional conservation of the original isochore pattern in the surviving population. Negative selection may also largely explain the GC increase accompanying the emergence of warm-blooded vertebrates. In conclusion, the neoselectionist theory not only provides a solution to the neutralist/selectionist debate but also introduces an epigenomic component in genome evolution.

Eugenie C. Scott and Nicholas J. Matzke, Biological design in science classrooms.

Although evolutionary biology is replete with explanations for complex biological structures, scientists concerned about evolution education have been forced to confront "intelligent design" (ID), which rejects a natural origin for biological complexity. The content of ID is a subset of the claims made by the older "creation science" movement. Both creationist views contend that highly complex biological adaptations and even organisms categorically cannot result from natural causes but require a supernatural creative agent. Historically, ID arose from efforts to produce a form of creationism that would be less vulnerable to legal challenges and that would not overtly rely upon biblical literalism. Scientists do not use ID to explain nature, but because it has support from outside the scientific community, ID is nonetheless contributing substantially to a long-standing assault on the integrity of science education.

Science Journalism: A Bias in Favour of Truth

 
Peter McKnight is a science journalist who writes for The Vancouver Sun. Don't hold that against him, he's actually one of the most thoughtful science journalist around. Readers may recall that we had a discussion about his views concerning Marus Ross and his Ph.D. in geology [Peter McKnight of the Vancouver Sun Weighs in on the Marcus Ross Incident and Peter McKnight on the Marcus Ross Issue].

I disagreed with Peter back then but I agree with his latest column from last Saturday [what we need here is a bias in favour of truth]. McKnight argues that the tendency toward balance and fairness in journalism is hurting science journalism. When it comes to science there aren't always two legitimate sides to every story. For example, in the evolution vs. creationism controversy, journalists do not have an obligation to give equal time to creationist nonsense.

Similarly, when I write about evolution and creationism, I am invariably accused of bias -- a lack of balance -- for explaining that evolution is a scientific theory and creationism is not. To repair this problem, certain letter writers tell me that I should simply present both positions equally, without editorial comment, and let my readers decide the truth.

Doing that would amount to an abdication of my role as a columnist, since I have a responsibility to offer an opinion. It would also represent an affront to science, but I understand where my letter writers are coming from; journalism has long promoted the view that journalists ought to present both sides in a dispute and keep their opinions to themselves.

I agree. Science journalists should not be simple reporters of fact. They need to interpret those facts and put them in context. They need to contribute a certain added value to their reports, otherwise we might just as well read the original press releases or the abstract of the paper.

Despite this evidence from more than a century ago, false balance came to dominate journalism and still exists today. Many reasons for this have been identified: In our increasingly partisan era, journalists are ultra-sensitive to accusations of bias, so they ensure balance to ward off such allegations; some journalists don't have the time -- and some are too lazy -- to conduct a thorough investigation of an issue, so it's easier to just present competing opinions; and some journalists don't have the expertise to filter through various opinions and determine which ones are based on solid evidence.

This last reason is particularly common in science journalism, since few journalists outside of publications like Scientific American have backgrounds in science. Yet, remarkably, former New York University sociologist Dorothy Nelkin noted in her book Selling Science that some journalists are hostile to science reporters who have science backgrounds, because "journalists trained extensively in science may adopt the values of scientists and lose the ability to be critical."

I can understand why average journalists are afraid of real science journalists. It's because good science journalists can do something that the typical non-science journalist can't do. That goes against the fundamental credo of the profession; namely, that journalists can cover any story because they're trained to report the facts. (Are they also hostile to those journalists who are knowledgeable about the law, medicine, or business—or is it just science?)

I agree with Peter McKnight about the need for science journalists to inject their own (informed) opinion into their articles. But I want to take it one step further. From my perspective, the most annoying science articles are not the ones that give inappropriate "balance" to the ideas of kooks. The worst ones are those that show no informed skepticism at all but merely report whatever the scientific paper says. I want my science journalists to do some digging from time to time, which is why I criticized an article in the "TRUTH" issue of SEED last month [Silent Mutations and Neutral Theory].

It's complicated. I want science journalists to give us an informed opinion. I don't want them to go out of their way to present contrary opinions just for the sake of "balance" and "fairness." On the other hand, I do want them to present contrary points of view when the news they're covering is itself biased and unfair.

It's tough to be a science journalist these days. They don't get no respect from either their journalist colleagues, or their science colleagues!

[Hat Tip: Jason Spaceman on talk.origins]

John Wise on Science and the Supernatural

 
John Wise is a Professor of Biology at Southern Methodist University in Dallas, Texas (USA). He writes on the campus website [Intelligent Design is not science: why this matters].

Because science gives us methods to accurately understand and manipulate the world we live in. Few people would dispute that our present scientific understanding of the physical world has led to a tremendously long list of advances in medicine, technology, engineering, the structure of the universe and the atom, and on and on. The list is nearly endless, but it does not include everything. Science can tell us only what is governed by natural forces. Miracles are extra-ordinary events; gods are super-natural beings.

Are there reasonable philosophical arguments that can be made for the existence of God? Certainly. Are there reasonable philosophical arguments that can be made that God does not exist? Yes. Is there scientific evidence that answers either of these great questions one way or another? None that holds up to close scrutiny. Collins has no more scientific evidence that God exists than Dawkins has that God does not. Their evidence is philosophical, not scientific. Philosophy can encompass these issues, science cannot.

Okay, let's examine that argument. Science deals with the natural world, that's fair enough. Religion deals with the supernatural world so it's outside of science. That's also a fair statement. The question is, is there such a thing as a "supernatural world" and how can we learn anything about it?

We can deal with the natural world and we can at least imagine that there's a supernatural world beyond the reach of science. But there's a whole lot of middle ground that's being excluded here. Any religious claim that impinges on the natural world is subject to scientific analysis. That includes claims of miracles.

The only kind of religion that can be completely outside of science is one that believes in a God who never meddles in human affairs. Because as soon as that meddling occurs—answering prayers, for example—we scientists can legitimately ask whether the meddling is detectable or not.

Miracles either exist or they don't. If they do then we should have evidence for miracles. If there's no evidence then you should not believe in them. If you believe in miracles in the absence of evidence for their existence, then your belief is in conflict with science.

Professor Wise says that science can't prove the non-existence of God. That's true. In fact, we can't prove the non-existence of many things. We can't prove, for example, that astrology is completely false in every single case. What we can do is to limit its probability to such a small number that it makes no sense to believe in astrology. That's the power of science.

Professor Wise goes on to describe Professor Behe's testimony at the Dover trial in 2005.

Listen further to the transcripts of these hearings - they are astounding. Professor Behe, star witness for the ID proponents and Discovery Institute senior fellow, gave a Discovery Institute-approved definition of scientific theory in his testimony. Unfortunately for both Dr. Behe and the Discovery Institute, Eric Rothschild, the brilliant lawyer for the parents, asked Dr. Behe, "But you are clear, under your definition, the definition that sweeps in Intelligent Design, astrology is also a scientific theory, correct?" And Dr. Behe answered, "Yes, that's correct."

Is this what America wants and needs? A definition of science that is so weak and neutered that astrology qualifies?

Of course we don't want such a science. We want a science that rejects astrology because there's no evidence for it. We don't want astrologers to try and escape scientific scrutiny by claiming that astrology is outside of science, do we? We don't want astrologers to claim that their horoscopes are "miracles" and therefore just as legitimate as science.

Why is it that we feel very comfortable rejecting the ridiculous claims of astrology but we have to make special excuses to protect religion from close scientific scrutiny?

[Hat Tip: The Panda's Thumb]

Becoming Canadian

 
Jeffrey Shallit, a long time opponent of intelligent design creationism, is an American citizen living in Canada. Why doesn't he become a Canadian citizen?
[Towards a Canadian Republic]

My answer has always been the same: I'll seriously consider becoming a citizen when Canada removes one citizenship requirement: that I swear allegiance to "Her Majesty the Queen Elizabeth the Second, Queen of Canada, her Heirs and Successors".

As an American who is proud of the republican tradition (small "r" in "republican", please), the citizenship requirement that one swear allegiance to a person seems unappealingly feudal to me. Paul McCartney famously observed that the current Queen is a pretty nice girl, but that doesn't mean I want to swear allegiance to her.

It seems like an innocent enough anachronism to me.

But the more important question is how does Professor Shallit feel about pledging allegiance to a "thing" as in ....

I pledge allegiance to the flag of the United States of America, and to the Republic, for which it stands, one nation under God, indivisible, with liberty and justice for all.

Theme: ABO Blood Types

 
ABO Blood Types (Feb. 21, 2007)

Glycoproteins (Feb. 20, 2007)

Genetics of ABO Blood Types (Feb. 23, 2007)

Human ABO Gene (Feb. 22, 2007)

Nobel Laureates: Carl Ferdinand Cori and Gerty Theresa Cori

The Nobel Prize in Physiology or Medicine 1947.

"for their discovery of the course of the catalytic conversion of glycogen"



Carl Ferdinand Cori (1896-1984) and Gerty Theresa Cori (1896-1957) won the Nobel Prize in 1947 for their work on understanding the synthesis and degradation of glycogen. Their major contribution was understanding the importance of phosphorylated intermediates, especially the "Cori ester" glucose-1-phosphate [Monday's Molecule #25].

Professor Carl Cori and Doctor Gerty Cori. During the past decade the scientific world has followed your work on glycogen and glucose metabolism with an interest that has gradually increased to admiration. Since the discovery of glycogen by Claude Bernard ninety years ago, we have been almost totally ignorant of how this important constituent of the body is formed and broken down. Your magnificent work has now elucidated in great detail the extremely complicated enzymatic mechanism involved in the reversible reactions between glucose and glycogen. Your synthesis of glycogen in the test tube is beyond doubt one of the most brilliant achievements in modern biochemistry. Your discovery of the hormonal regulation of the hexokinase reaction would seem to lead to a new conception of how hormones and enzymes cooperate.

In the name of the Caroline Institute I extend to you hearty congratulations on your outstanding contribution to biochemistry and physiology.

Cori and Cori are one of the few husband and wife teams to receive the Nobel Prize. They worked at Washington University in St. Louis, MO (USA).

Glycogen Degradation/Utilization

 
Glucose is stored as the intracellular polysaccharides starch and glycogen. Starch occurs mostly in plants. Glycogen is an important storage polysaccharide in bacteria, protists, fungi and animals. Glycogen is stored in large granules. In mammals, these granules are found in muscle and liver cells. In electron micrographs, liver glycogen appears as clusters of cytosolic granules with a diameter of 100 nm—much larger than ribosomes. The enzymes required for synthesis of glycogen are found in muscle and liver cells [Glycogen Synthesis]. Those same cells contain the enzymes for glycogen degradation.

The glucose residues of starch and glycogen are released from storage polymers through the action of enzymes called polysaccharide phosphorylases: starch phosphorylase (in plants) and glycogen phosphorylase (in many other organisms). These enzymes catalyze the removal of glucose residues from the ends of starch or glycogen. As the name implies, the enzymes catalyze phosphorolysis—cleavage of a bond by group transfer to an oxygen atom of phosphate. In contrast to hydrolysis (group transfer to water), phosphorolysis produces phosphate esters. Thus, the first product of polysaccharide breakdown is α-D-glucose 1-phosphate, not free glucose.


Glucose 1-phosphate is one of the precursors required for glycogen synthesis. It is the "Cori ester" [Monday's Molecule] discovered by Carl Cori and Gerty Cori [Nobel Laureates: Carl Cori and Gerty Cori]. The Cori's also discovered and characterized glycogen phosphorylase.

In order for glucose 1-phosphate to be used in other pathways it has to be converted to glucose 6-phosphate by the enzyme phosphoglucomutase. This is the same enzyme that's used in the synthesis of glycogen from glucose 6-phosphate.

Glucose 6-phosphate can be oxidzed by the glycolysis pathway to produce ATP. This is what happens in muscle cells. Glucose is stored as glycogen during times of rest but during exercise the glycogen is broken down to glucose 6-phosphate and glycolysis is activated. The resulting ATP is used in muscle activity.

Obviously, there has to be a balance between the synthesis and degradation of glycogen and this balance is maintained by regulating the activities of the biosynthesis and degradation enzymes. This regulation occurs at many levels. Regulation by hormones is one of the classic examples of a signal transduction pathway in mammals.

[©Laurence A. Moran. Some of the text is from Principles of Biochemistry 4th ed. ©Pearson/Prentice Hall]

Glycogen Synthesis

All cells are capable of making glucose. The pathways is called gluconeogenesis and the end product is not actually glucose but a phosphorylated intermediate called glucose-6-phosphate.

Glucose-6-phosphate (G6P) serves as the precursor for synthesis of many other compounds such as the ribose sugars needed in making DNA and RNA. The only organisms that make free glucose are multicellular organisms, such as animals, that secrete it into the circulatory system so it can be taken up and used by other cells (Glucose-6-phosphate cannot diffuse across the membrane so it's retained within cells.)

In times of plenty, G6P may not be needed in further biosynthesis reactions so cells have evolved a way of storing, or banking, excess glucose. The stored glucose molecules can then be retrieved when times get tough. Think of bacteria growing in the ocean, for example. There may be times when an abundant supply of CO₂ combined with a surplus of inorganic energy sources (e.g., H₂S) allows for synthesis of lots of G6P. These cells can store the excess G6P by making glycogen—a polymer of glucose residues.

Glycogen consists of long chains of glucose molecules joined end-to-end through their carbon atoms at the 1 and 4 positions. The chains can have many branches. Completed chains can have up to 6000 glucose residues making glycogen one of the largest molecules in living cells.

The advantage of converting G6P to glycogen is that it avoids the concentration effects of having too many small molecules floating around inside the cell. By compacting all these molecules into a single large polymer the cell is able to form large granules of stored sugar (see photo above).

The first step in the synthesis of glycogen is the conversion of glucose-6-phosphate to glucose-1-phosphate by the action of an enzyme called phosphoglucomutase. (Mutases are enzymes that rearrange functional groups, in this case moving a phosphate from the 6 position of glucose to the 1 position.) The glycogen synthesis reaction requires adding new molecules that will be connected to the chain through their #1 carbon atoms so this preliminary reaction is required in order to "activate" the right end of the glucose residue.
Glucose-1-phosphate is the "Cori ester" [Monday's Molecule #25] that was discovered by Carl Cori and Gerty Cori while they were working out this pathway [Nobel Laureates: Carl Cori and Gerty Cori].

The next step is the conversion of glucose-1-phosphate to the real activated sugar, UDP-glucose. The enzyme is UDP-glucose pyrophosphorylase and the UDP-glucose product is similar to many other compound that are activated by attaching a nucleotide. In some bacteria, the activated sugar is ADP-glucose but the enzyme is the same as that found in eukaryotes. ADP-glucose is the activated sugar in plants, as well. In plants the storage molecules are starch, not glycogen, but the difference is small (starch has fewer branches).

Glycogen synthesis is a polymerization reaction where glucose units in the form of UDP-glucose are added one at a time to a growing polysaccharide chain. The reaction is catalyzed by glycogen synthase.



[©Laurence A. Moran. Some of the text is from Principles of Biochemistry 4th ed. ©Pearson/Prentice Hall]

Mendel's Garden #14

 

Mendel's Garden #14 has been posted on Epigenetic News.

Nobel Laureate: Walther Hermann Nernst

 

The Nobel Prize in Chemistry 1920.

"in recognition of his work in thermochemistry"

Walther Hermann Nernst won the Nobel Prize in 1920 for his work in understanding the energy of reactions. The main work is summarized in the presentation speech,

Before Nernst began his actual thermochemical work in 1906, the position was as follows. Through the law of the conservation of energy, the first fundamental law of the theory of heat, it was possible on the one hand to calculate the change in the evolution of heat with the temperature. This is due to the fact that this change is equal to the difference between the specific heats of the original and the newly-formed substances, that is to say, the amount of heat required to raise their temperature from 0° to 1° C. According to van't Hoff, one could on the other hand calculate the change in chemical equilibrium, and consequently the relationship with temperature, if one knew the point of equilibrium at one given temperature as well as the heat of reaction.

The big problem, however, that of calculating the chemical affinity or the chemical equilibrium from thermochemical data, was still unsolved.

With the aid of his co-workers Nernst was able through extremely valuable experimental research to obtain a most remarkable result concerning the change in specific heats at low temperatures.

That is to say, it was shown that at relatively low temperatures specific heats begin to drop rapidly, and if extreme experimental measures such as freezing with liquid hydrogen are used to achieve temperatures approaching absolute zero, i.e. in the region of -273° C, they fall almost to zero.

This means that at these low temperatures the difference between the specific heats of various substances comes even closer to zero, and thus that the heat of reaction for solid and liquid substances practically becomes independent of temperature at very low temperatures.

Today, Nernst is known for his other contributions to thermodynamics. In biochemistry he is responsible for the Nernst equation that relates standard reduction potentials and Gibbs free energy.

The Nernst Equation

 
In standard oxidation-reduction reactions you can usually tell whether a given compound will donate or receive electrons by looking at the standard reduction potential (ΔE°ʹ) [Oxidation-Reduction Reactions]. This is a big step toward understanding how electrons flow in biochemical reactions but we would like to know more about the energy of oxidation-reduction reactions since they are the fundamental energy-producing reactions in the cell.

The standard reduction potential for the transfer of electrons from one molecular species to another is related to the standard Gibbs free energy change (ΔG°ʹ) for the oxidation-reduction reaction by the equation

where n is the number of electrons transferred and ℱ (F) is Faraday’s constant (96.48 kJ V^-1 mol^-1). ΔE°ʹ is defined as the difference in volts between the standard reduction potential of the electron-acceptor system and that of the electron-donor system. The Δ (delta) symbol indicates a change or a difference between two values.

You may recall that electrons tend to flow from half-reactions with a more negative standard reduction potential to those with a more positive one. For example, in the pyruvate dehydrogenase reaction electrons flow from pyruvate (E°' = -0.48 V) to NAD⁺ (E°' = -0.32 V). We can calculate the change in standard reduction potentials; it's equal to +0.16 V [-0.32 - (-0.48) = +0.16].

Now we can calculate a standard Gibbs free energy change (ΔG°ʹ) for the electron transfer part of the pyruvate dehydrogenase reaction. Two electrons are transferred from pyruvate to NAD⁺ so the standard Gibbs free energy change is -31 kJ mol^-1 [-2(96.48)(0.16)]. This turns out to be a significant amount of energy that could be captured by the NADH molecule but you have to keep in mind that this is a standard Gibbs free energy change and conditions inside the cell are far from standard. The biggest difference is that standard Gibbs free energy changes are computed with equal concentrations of reactants and products at a concentration of 1M—about a thousand times higher than the concentrations inside the cell where, in addition, the concentrations of reactants and products are not equal.

Fortunately, we have a way of adjusting the values of the Gibbs free energy change and the change in the standard reduction potential to account for the actual concentrations inside the cell. The standard Gibbs free energy change is related to the equilibrium constant of a reaction K_eq by the equation

Just as the actual Gibbs free energy change for a reaction is related to the standard Gibbs free energy change by this equation, an observed difference in reduction potentials (ΔE) is related to the difference in the standard reduction potentials (ΔE°') by the Nernst equation.

By combining equations for ΔG°ʹ we get
For a reaction involving the oxidation and reduction of two molecules, A and B,
the Nernst equation is
where [A_ox] is the concentration of oxidized A inside the cell. The Nernst equation tells us the actual difference in reduction potential (ΔE) and not the artificial standard change in reduction potential (ΔE°ʹ).

At 298 K (25° C), this equation reduces to
where Q represents the ratio of the actual concentrations of reduced and oxidized species. To calculate the electromotive force of a reaction under nonstandard conditions, use the Nernst equation and substitute the actual concentrations of reactants and products. Keep in mind that a positive E value indicates that an oxidation-reduction reaction will have a negative value for the standard Gibbs free energy change.

The Nernst equation is very famous but it's actually not very useful. The problem is that many of the oxidation-reduction reactions take place within an enzyme complex such as the pyruvate dehydrogenase complex. The concentrations of the reactants and products are difficult to calculate under such conditions. That's why we usually use the standard reduction potentials instead of the actual reduction potentials, keeping in mind that these are only approximations of what goes on inside the cell.

Let's see what happens when we calculate the standard Gibbs free energy change for the reaction where NADH donates electrons to oxygen. Oxygen serves as an electron sink for getting rid of excess electrons [Oxidation-Reduction Reactions].

NAD⁺ is reduced to NADH in coupled reactions where electrons are transferred from a metabolite (e.g., pyruvate) to NAD⁺. The reduced form of the coenzyme (NADH) becomes a source of electrons in other oxidation-reduction reactions. The Gibbs free energy changes associated with the overall oxidation-reduction reaction under standard conditions can be calculated from the standard reduction potentials of the two half-reactions using the equations above.

As an example, let’s consider the reaction where NADH is oxidized and molecular oxygen is reduced. This represents the available free energy change during membrane-associated electron transport. This free energy is recovered in the form of ATP synthesis.

The two half-reactions from a table of standard reduction potentials are,

and
Since the NAD⁺ half-reaction has the more negative standard reduction potential, NADH is the electron donor and oxygen is the electron acceptor. The net reaction is
and the change in standard reduction potential is

Using the equations described above we get

What this tells us is that a great deal of energy can be released when electrons are passed from NADH to oxygen provided the conditions inside the cell resemble those for the standard reduction potentials (they do). The standard Gibbs free energy change for the formation of ATP from ADP + P_i is -32 kJ mol^-1 (the actual free-energy change is greater under the conditions of the living cell, it's about -45 kJ mol^-1). This strongly suggests that the energy released during the oxidation of NADH under cellular conditions is sufficient to drive the formation of several molecules of ATP. Actual measurements reveal that the oxidation of NADH can be connected to formation of 2.5 molecules of ATP giving us confidence that the theory behind oxidation-reduction reactions is sound.

[©Laurence A. Moran. Some of the text is from Principles of Biochemistry 4th ed. ©Pearson/Prentice Hall]

A Rational Canadian Speaks Out

 
Dan Gardner wrote a column in the Ottawa Citizen [Those fanatical atheists]. He makes so much sense I'm just going to quote several paragraphs and let everyone see what every rational person should be saying. This is the effect Richard Dawkins is having and I think it's about time.

Then there's the problem on the other side -- among the atheists such as Richard Dawkins who have been labelled "fanatics." Now, it is absolutely true that Dawkins' tone is often as charming as fingernails dragged slowly down a chalkboard. But just what is the core of Dawkins' radical message?

Well, it goes something like this: If you claim that something is true, I will examine the evidence which supports your claim; if you have no evidence, I will not accept that what you say is true and I will think you a foolish and gullible person for believing it so.

That's it. That's the whole, crazy, fanatical package.

When the Pope says that a few words and some hand-waving causes a cracker to transform into the flesh of a 2,000-year-old man, Dawkins and his fellow travellers say, well, prove it. It should be simple. Swab the Host and do a DNA analysis. If you don't, we will give your claim no more respect than we give to those who say they see the future in crystal balls or bend spoons with their minds or become werewolves at each full moon.

And for this, it is Dawkins, not the Pope, who is labelled the unreasonable fanatic on par with faith-saturated madmen who sacrifice children to an invisible spirit.

This is completely contrary to how we live the rest of our lives. We demand proof of even trivial claims ("John was the main creative force behind Sergeant Pepper") and we dismiss those who make such claims without proof. We are still more demanding when claims are made on matters that are at least temporarily important ("Saddam Hussein has weapons of mass destruction" being a notorious example).

So isn't it odd that when claims are made about matters as important as the nature of existence and our place in it we suddenly drop all expectation of proof and we respect those who make and believe claims without the slightest evidence? Why is it perfectly reasonable to roll my eyes when someone makes the bald assertion that Ringo was the greatest Beatle but it is "fundamentalist" and "fanatical" to say that, absent evidence, it is absurd to believe Muhammad was not lying or hallucinating when he claimed to have long chats with God?

[Hat Tip: PZ Myers]

Oxidation-Reduction Reactions

 
Biochemical reactions are just a complicated form of organic chemistry. Living organisms have evolved enzymes that make these reactions go faster but the underlying chemistry is unchanged.

Cells are constantly having to deal with the problem of shuffling electrons and channeling them to the right place. You might be familiar with the classic fuel metabolism example of glycolysis where the breakdown of glucose to CO₂ releases electrons. When a reaction results in the loss of electrons it's called an oxidation reaction. When electrons are gained it's a reduction reaction. Oxidations and reductions always go together since electrons are passed from one molecule to another.


Loss of Electrons is Oxidation (LEO)


Gain of Electrons is Reduction (GER)


LEO says GER


Oxidation Is Loss of electrons (OIL)


Reduction Is Gain of electrons (RIG)


OIL RIG

During glycolysis, the electrons that are released have to be deposited in some sort of electron sink and expelled as waste. If a cell couldn't get rid of its electrons it would build up a huge negative charge.

Oxygen is the electron sink in mammalian fuel metabolism. A molecule of oxygen takes up electrons and combines with protons to make water. The easiest way to see this is to draw the molecules as Lewis structures showing the valence electrons (Pushing Electrons).

There are sixteen electron on each side of this equation for the reduction of molecular oxygen. Remember, reduction is a gain of electrons. This is a half-reaction, there is no corresponding oxidation that provides the electrons so this isn't a valid oxidation-reduction reaction. It just shows the reduction part.

None of the reactions of glycolysis result in the direct reduction of molecular oxygen. In all cases, the release of electrons when glucose is broken down to CO₂ is coupled to temporary electron storage in various coenzymes. We have already encountered several of these electron storage molecules such as ubiquinone, FMN & FAD, and NADPH.

We discussed a simple electron transport chain where electrons were passed from pyruvate to NAD⁺ in the pyruvate dehydrogenase reaction. This is a classic oxidation-reduction reaction.

How do we know which direction electron are going to flow? For example, if ubiquinone is reduced to ubiquinol by acquiring two electrons then where do the electrons come from? Can NADH pass electrons to ubiquinone or does ubiquinol pass its two electrons to NAD⁺? And where does FAD⁺ fit? Can it receive electrons from NADH?

The answer is related to the reduction potential of the various electron carriers. In order to understand reduction potentials we need to learn a little inorganic chemistry.

The reduction potential of a reducing agent is a measure of its thermodynamic reactivity. Reduction potential can be measured in electrochemical cells. An example of a simple inorganic oxidation-reduction reaction is the transfer of a pair of electrons from a zinc atom (Zn) to a copper ion (Cu²⁺) as shown below. When a pair of electrons is removed from zinc it leaves a zinc ion that's deficient in two negative charges (Zn²⁺). These electrons can be taken up by a copper ion (Cu²⁺) resulting in a copper atom (Cu) with no charge.

This reaction can be carried out in two separate solutions that divide the overall reaction into two half-reactions. At the zinc electrode, two electrons are given up by each zinc atom that reacts (the reducing agent). The electrons flow through a wire to the copper electrode, where they reduce Cu2+ (the oxidizing agent) to metallic copper. A salt bridge, consisting of a tube with a porous partition filled with electrolyte, preserves electrical neutrality by providing an aqueous path for the flow of nonreactive counterions between the two solutions. The flow of ions and the flow of electons are separated in an electrochemical cell. Electron flow (i.e., electric energy) can be measured using a voltmeter.
The direction of the current through the circuit in the figure indicates that Zn is more easily oxidized than Cu (i.e., Zn is a stronger reducing agent than Cu). The reading on the voltmeter represents a potential difference—the difference between the reduction potential of the reaction on the left and that on the right. The measured potential difference is the electromotive force.

It is useful to have a reference standard for measurements of reduction potentials just as in measurements of Gibbs free energy changes. For reduction potentials, the reference is not simply a set of reaction conditions but a reference half-reaction to which all other half-reactions can be compared. The reference half-reaction is the reduction of H+ to hydrogen gas (H2). The reduction potential of this half-reaction under standard conditions (E̊) is arbitrarily set at 0.0 V. The standard reduction potential of any other half-reaction is measured with an oxidation-reduction coupled reaction in which the reference half-cell contains a solution of 1M H+ and 1 atm H2(gaseous), and the sample half-cell contains 1 M each of the oxidized and reduced species of the substance whose reduction potential is to be determined. Under standard conditions for biological measurements, the hydrogen ion concentration in the sample half-cell is (pH 7.0). The voltmeter across the oxidation-reduction couple measures the electromotive force, or the difference in the reduction potential, between the reference and sample half-reactions. Since the standard reduction potential of the reference half-reaction is 0.0 V, the measured potential is that of the sample half-reaction.
The table below gives the standard reduction potentials at pH 7.0 (E̊́) of some important biological half-reactions. Electrons flow spontaneously from the more readily oxidized substance (the one with the more negative reduction potential) to the more readily reduced substance (the one with the more positive reduction potential). Therefore, more negative potentials are assigned to reaction systems that have a greater tendency to donate electrons (i.e., systems that tend to oxidize most easily).

It's important to note the direction of all these reactions is written in the form of a reduction or gain of electrons. That's not important when it comes to determining the direction of electron flow. For example, note that the reduction of acetyl-CoA to pyruvate is at the top of the list (E̊́= -0.48 V). This is the reaction catalyzed by pyruvate dehydrogenase. Electrons released by the oxidation of pyruvate will flow to any half reaction that has a higher (less negative) standard reduction potential. In this case the electrons end up in NADH (E̊́ = -0.32 V).

The reduction of oxygen is way down at the bottom of the list. That's why it's an effective electron sink for gettng rid of electrons.

Now we'd like to know something about the thermodynamics of these electron transport reactions so we can find out how much energy is available to do useful work. This will lead us to the Nobel Laureate for April 25th.

[©Laurence A. Moran. Some of the text is from Principles of Biochemistry 4th ed. ©Pearson/Prentice Hall]

Pushing Electrons

 
Biochemistry, as the name implies, is concerned with the chemistry of life. The chemistry part is mostly organic chemistry and organic chemistry is mostly about pushing electrons.

Covalent bonds are formed when the nuclei of two atoms share a pair of electrons. The "bond" is actually a cloud of electrons orbiting the two nuclei. The atoms are held together because neither one is stable without the shared electrons. The reactions in organic chemistry and biochemistry can be thought of as simple rearrangements of electrons to form new covalent bonds and break apart old ones. In this sense it's all about pushing electrons from one location to another.

The best way to think about covalent bonds is to visualize the electrons in the other shell of atoms. Those are the ones that participated in bonding. The outer shell electrons are often referred to as the valence electrons. The first shell of electrons can only hold two electrons. Hydrogen atoms have a single electron so in order to form a stable compound they have to combine with something that supplies an electron that can be shared. The simplest of these compounds is a molecule of hydrogen (H₂).

When two atoms of hydrogen combine to form H₂ both atoms succeed in filling their outer shells with two electron by sharing electrons. The shared pair of electrons is the covalent bond. The type of structures shown in the equation are called Lewis Structures. The dots represent electrons in the outer shell of the atom.

The inner electron shell can only hold two electrons but all other shells can accommodate eight electrons. The atomic number of oxygen is 8, which means that it has two electrons in the inner shell and only six in the outer shell. It needs to combine with two other atoms in order to get enough electrons to fill the outer shell.
In this example, oxygen with six electrons in the valence shell is combining with two hydrogen atoms to form water (H₂O). By sharing electrons both the hydrogen atoms and the oxygen atom will complete their outer shells of electrons—hydrogen with two electrons and oxygen with eight.

Sometimes atoms can share more than a pair of electrons. For example, when two atoms of oxygen combine to form the oxygen molecule (O₂) there are four electrons shared between the two atoms. This results in a double bond between them.
Carbon has an atomic number of 6, which means that it has two electrons in the inner shell and only four electrons in the outer shell. Carbon can combine with four other atoms to fill up its outer shell with eight electrons. This ability to combine with several different atoms is one of the reasons why carbon is such a versatile atom. The structure of ethanol (CH₃CH₂OH, left) illustrates this versatility. Note that each atom has a complete outer shell of electrons and that each carbon atom is covalently bonded to four other atoms.

Biochemical reactions are a lot more complicated but once you understand the concept of electron pushing it becomes relatively easy to make sense of the reaction mechanisms seen in textbooks. The only additional information you need is the knowledge that some atoms can carry an extra electron and this makes them a negatively charged ion (e.g., — O^-). Some stable atoms are missing an electron in their outer shell so this makes them a positively charged ion (e.g., — N⁺).

In many cases a proton (H⁺) is released from a compound leaving its electron behind. This proton has to combine with an atom that already has a pair of electrons in its outer shell (e.g., a base B:). Here's an example of the reaction mechanism for aldolase, one of the enzymes in the gluconeogenesis/glycolysis pathway.
The outline of the enzyme is shown in blue. One of the key concepts in biochemistry is that enzymes speed up reactions, in part, by supplying and storing electrons. In this case an electron withdrawing group (X) pulls electrons from oxygen and this weakens the carbon-oxygen double bond (keto group). Carbon #2, in turn, pulls an electron from carbon #3 weakening the C3-C4 bond that will be broken. (Aldolase cleaves a six-carbon compound into two three-carbon compounds as shown here. It also preforms the reverse reaction where two three-carbon compounds are combined to form a six-carbon compound.)

A basic residue in the protein (B) removes a proton from the -OH (hydroxyl) group to form a B-H covalent bond. This leaves an additional electron on the oxygen and it combines with one left on C4 to from a double bond. The red arrows show the movement of electrons in these reaction mechanisms.

The key point here is that biochemical reactions are just like those of all chemical reactions. They involve the movement of electrons to break and form covalent bonds.