Regulating Glycogen Metabolism

Mammalian glycogen stores glucose in times of plenty (after feeding, a time of high glucose levels) and supplies glucose in times of need (during fasting or in “fight-or-flight” situations). In muscle, glycogen provides fuel for muscle contraction. In contrast, liver glycogen is largely converted to glucose that exits liver cells and enters the bloodstream for transport to other tissues that require it [The Cori Cycle]. Both the mobilization and synthesis of glycogen are regulated by hormones.

The regulation of glycogen metabolism is a good way to introduce the idea of signal transduction. This is a very popular part of modern biochemistry. It's basically a way in which signals from outside the cell are transduced through a chain of molecules to affect a particular biochemical reaction. In this case, we'll examine how the hormones glucagon, epinephrine, and insulin regulate glycogen synthesis and glycogen degradation.

Let's look at glycogen synthesis. Glycogen synthase is the enzyme responsible for adding UDP-glucose to a growing chain of glycogen. There are two forms of this enzyme. The inactive form is called glycogen synthase b and it is phosphorylated (P). The active form is called glycogen synthase a and it does not carry a phosphate group. The activity of glycogen synthase is controlled by covalent modification just like pyruvate dehydrogenase [Regulating Pyruvate Dehydrogenase].

The phosphorlation of enzymes is performed by kinases. In this case it's a very common cellular kinase called protein kinase A (PKA). The complete name of the enzyme is cyclic AMP-dependent protein kinase A because its activity is regulated by a messenger molecule known as cyclic AMP (cAMP). Cyclic AMP is made from ATP by the enzyme adenylyl cyclase and it is degraded by the action of an enzyme called phosphodiesterase

When cAMP is present inside the cell it binds to protein kinase A and activates it so that it can phosphorylate glycogen synthase. This shuts down glycogen synthesis by deactivating the enzyme. The key to hormonal regulation is the effect of the hormones on the production of cAMP. This takes place on the cell surface when the hormone binds to a cell surface receptor molecule.

Insulin, glucagon, and epinephrine are the principal hormones that control glycogen metabolism in mammals. Insulin, a 51-residue protein is synthesized by the cells of the pancreas. It is secreted when the concentration of glucose in the blood increases. Thus, high levels of insulin are associated with the fed state of an animal. Insulin stimulates glycogen synthesis in the liver. This makes sense since high concentrations of glucose indicate that it's time to store it as glycogen.

Glucagon, a peptide hormone containing 29 amino acid residues, is secreted by the cells of the pancreas in response to a low blood glucose concentration. Glucagon restores the blood glucose concentration to a steady-state level by stimulating glycogen degradation. Only liver cells are rich in glucagon receptors, so glucagon is extremely selective in its target. The effect of glucagon is opposite that of insulin, and an elevated glucagon concentration is associated with the fasted state.

The adrenal glands release the catecholamine epinephrine (also known as adrenaline) in response to neural signals that trigger the fight-or-flight response. Epinephrine stimulates the breakdown of glycogen to glucose 1-phosphate, which is converted to glucose 6-phosphate. The increase in intracellular glucose 6-phosphate increases both the rate of glycolysis in muscle and the amount of glucose released into the bloodstream from the liver. Note that epinephrine triggers a response to a sudden energy requirement; glucagon and insulin act over longer periods to maintain a relatively constant concentration of glucose in the blood.

Epinephrine binds to β-adrenergic receptors of liver and muscle cells and to α1-adrenergic receptors of liver cells. The binding of epinephrine to β-adrenergic receptors or of glucagon to its receptors activates the adenylyl cyclase signaling pathway. The second messenger, cyclic AMP (cAMP), then activates protein kinase A.

For now let's just take it as a given that glucagon and epinephrine trigger cAMP synthesis and this leads to shutting down of glycogen synthesis.


In addition to blocking glycogen synthesis, these hormones stimulate glycogen degradation. The glycogen degradation enzyme is called glycogen phosphorylase and it comes in two forms. Glycogen phosphorylase a is the active form and it's phosphorylated (it has an attached phosphate group). Glycogen phosphorylase b is the unphosphorylated form of the enzyme and it's inactive. Note the reciprocal relationship of the glycogen synthase and glycogen degradation enzymes. When both are phosphorylated, glycogen degradation is active and glycogen synthesis is not. When both are dephosphorylated, glycogen synthesis is active and glycogen degradation is blocked. This suggests a similar mechanism of regulation for the two enzymes.

The phosphorylation of glycogen phosphorulase is carried out by a kinase enzyme. In this case it's a specific kinase called phosphorylase kinase. Phosphorylase kinase is itself subject to activation by phosphorylation. The kinase that does this is our friend protein kinase A. Thus, epinephrine and glucagon will stimulate glycogen degradation in addition to stopping glycogen synthesis.



For every kinase there's a phosphatase that removes phosphate groups from proteins. Recall that insulin is released when glucose levels in the blood are high. The effect of insulin is the exact opposite of the effect of glucagon and epinephrine. Insulin binds to a cell surface receptor and triggers a pathway that leads to activation of protein phosphatase-1. This enzyme dephosphorylates the three enzymes shown above leading to activation of glycogen synthesis and deactivation of glycogen degradation. Insulin causes glucose to be stored as glycogen.



These kinds of kinase/phosphatase cascades are very common in eukaryotes. Believe it or not, this is one of the simpler examples.

Now, let's return to the effect of the hormone on cAMP synthesis. This is the key part of any signaling pathway and it's best illustrated by using a general model based on cAMP production. (There are other types of signaling pathways.)



The details aren't important unless you're seriously into signaling—like 50% of all biochemistry graduate students these days. Hormone binds to a cell surface receptor. The signal is transferred through the cell membrane to the inside part of the receptor molecule. This interacts with a G protein so that when hormone binds, the G protein is activated.

G protein then diffuses to the membrane bound adenylyl cyclase molecule and, when the two proteins connect, the activity of adenylyl cyclase is stimulated and cAMP is produced. This leads to activation of protein kinase A. The stimulatory effect of the signal transduction pathway is transient because cAMP is rapidly degraded by phosphodiesterase. Thus, hormone must usually be continuously present in order to get stimulation.

There are other hormones that inhibit cAMP production by activating different G proteins (G_i) that block adenylyl cyclase.

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

Nicole Vienneau Has Gone Missing in Syria

 
Our friends are devastated because their niece, Nicole Vienneau, is missing in Syria. Her brother has a website with all the information [My Sister, Nicole Vienneau, Has Gone Missing in Syria].

My sister, Nicole Vienneau, has been missing in Syria since April 1st (40 days), near the town of Hama, while on a day-trip to see Qasr Ibn Wardan (a nearby castle) and the "Beehive Houses". We found her gear at the Cairo Hotel, but no sign of her after that.

If you have any details or contacts in the area, please contact me at mattv99@hotmail.com.

There's little chance that readers of Sandwalk can help but just in case please contact him immediately if you have any information.

Eye on DNA

 


Hsien-Hsien Lei, formerly of Genetics & Health, has a new blog called Eye on DNA. I've been reading it for a week or so and it looks really cool. Check it out.

Hsein-Hsein Lei (pronounced shen-shen lay) has a Ph.D. in epidemiology. She's ultimately interested in making everyone more healthy but she also wants everyone to know how your genes work. Right now she works out of London (UK) so North Americans can read her posting first thing in the morning!

City Lights Make Birds Sing at Night

 
Friday's Urban Legend: PROBABLY FALSE

BBC News reports that "Robins in urban areas are singing at night because it is too noisy during the day, researchers suggest" [City birds sing for silent nights].

Scientists from the University of Sheffield say there is a link between an area's daytime noise levels and the number of birds singing at night.

Until now, light pollution had been blamed because it was thought that street lights tricked the birds into thinking it was still daytime.

The findings are published in the Royal Society journal Biology Letters.

It turns out that it's not because of night lights that the birds are singing. It's because they can't make themselves heard over the din of city traffic so they wait 'till the dead of night to start singing. That way they get to annoy everyone around them.

I wonder if that's why people talk on cell phones when they're sitting on a quiet commuter train?

Lose Weight: Emigrate to Canada

 

Satellites solve mystery of low gravity over Canada

If it seems Canadians weigh less than their American neighbours, they do—but not for the reasons you might think. A large swath of Canada actually boasts lower gravity than its surroundings.

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.