ASBMB Core Concepts in Biochemistry and Molecular Biology: Homeostasis

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Better BiochemistryThe American Society for Biochemistry and Molecular Biology (ASBMB) has decided that the best way to teach undergraduate biochemistry is to concentrate on fundamental principles rather than facts and details. This is an admirable goal—one that I strongly support.

Last October I discussed the core concepts proposed by Tansey et al. (2013) [see Fundamental Concepts in Biochemistry and Molecular Biology]. The five concepts are:

1. evolution [ASBMB Core Concepts in Biochemistry and Molecular Biology: Evolution ]
2. matter and energy transformation [ASBMB Core Concepts in Biochemistry and Molecular Biology: Matter and Energy Transformation]
3. homeostasis [ASBMB Core Concepts in Biochemistry and Molecular Biology: Homeostasis]
4. biological information [ASBMB Core Concepts in Biochemistry and Molecular Biology: Biological Information]
5. macromolecular structure and function [ASBMB Core Concepts in Biochemistry and Molecular Biology: Molecular Structure and Function]

It's one thing to advocate teaching core concepts but it's quite another to correctly identify what needs to be taught. I wasn't very happy about the way Tansey et al (2013) described the core concept of evolution [ASBMB Core Concepts in Biochemistry and Molecular Biology: Evolution].

I wasn't much happier with "matter and energy transformation" [ASBMB Core Concepts in Biochemistry and Molecular Biology: Matter and Energy Transformation].

Let's look at the third foundational concept, Homeostasis. "Homeostasis" isn't a word that I used anywhere in my Principles of Biochemistry textbook so I checked some other textbooks.

It's mentioned once in Lehninger where it refers to the maintenance of relatively constant level of glucose in our blood. It's discussed in Stryer in the context of "caloric homeostasis" as described on page 791.

At the biochemical level, how does an organism know when to eat and when to refrain from eating? The ability to maintain adequate but not excessive energy stores is called caloric homeostasis or energy homeostasis.

The same idea is mentioned in Garrett & Grisham where homeostasis refers exclusively to the concentration of fuels in human blood. None of these books treat homeostasis, per se, as a fundamental core concept of biochemistry.

In Voet & Voet there's a section on metabolic regulation that describes several reasons why organisms need to maintain steady-state concentrations of metabolites (= homeostasis).

1. In an open system, such as metabolism, the steady state is the state of maximum thermodynamic efficiency.
2. Many intermediates participate in more than one pathway, so that changing their concentrations may disturb a delicate balance.
3. The rate at which a pathway can respond to a control signal slows if large changes in intermediate concentrations are involved.
4. Large changes in intermediate concetrations may have deleterious effects on cellular osmotic properties.

Here's what the ASBMB committee says about homeostasis.

Biological systems operate under a relatively narrow and controlled set of conditions; as such, there is a need to maintain rigorous control over the concentrations of metabolites and small molecules in the cell. The cell is the basic physical unit of all organisms in that it creates a homeostatically controlled environment for rigorously maintaining the balance of energetically favorable and unfavorable chemical and physical processes within the confines of the cell as required for sustaining the life of the cell.

I'm not sure I agree with the statement that "biological systems operate under a relatively narrow and controlled set of conditions." Think about all the perennial plants in Ontario, for example. The conditions under which they operate range from hot sunny days in summer to freezing cold overcast days in the middle of winter. Similarly, the range of conditions under which many bacterial species operate can vary enormously. Many organisms can survive in an oxygen environment or in the complete absence of oxygen.

Many species have cells that carry out highly specialized functions with very different metabolic pathways than other cells. Cyanobacteria have heterocysts, reptiles have red blood cells, and mushrooms have cells devoted to making spores. I'm not certain that "homeostasis" is the best word to describe the way most species operate.

It might be better to talk about "regulation."

Tansey et al. continue with ...

Linked Steady State Processes and Homeostasis

Homeostasis is ultimately dictated by two laws of the thermodynamics: 1) Exergonic processes in the homeostatic environment of the cell must lead to a net loss in Gibbs free energy (ΔG < 0). Any favorable reaction must expend the capacity to do chemical work, as quantified by the Gibbs free energy. 2) Any exergonic reaction or process must ultimately lead to an increase in entropy or net “disorder” of the universe (ΔS > 0).

I believe that most metabolic reactions inside the cell are near-equilbrium reactions—a fundamental concept in my book. What this means is that ΔG is zero for a large number of reactions. They are neither exergonic not endergonic. The rate of the reaction is the same in both directions so in one direction there will likely be a positive change in entropy and in the other direction it will be negative. If what I believe is correct, then the description of a fundamental concept by Tansey et al. is irrelevant or misleading.

Biological homeostasis is largely maintained by systems of irreversible nonequilibrium steady-state reactions, although rapid equilibrium reactions (such as occur with cell buffers, including pH buffers and oxygen buffers like Hb and Mb) contribute to homeostasis. While all biochemical reactions are “reversible” (some more so than others on a temporal scale) and tend toward equilibrium, the overall chemical system in a cell is maintained in a state with nonequilibrium steady state concentrations of reactants and products.

It's true that there are some enzymatic reactions that are regulated so that they are never allowed to reach equilibrium. These are the metabolically irreversible reactions. A good example is ATP hydrolysis.

If ATP hydrolysis reactions were allowed to reach equilibrium then you could not get energy from the hydrolysis of ATP since ΔG = 0. This is a fundamental concept but I'm not sure that "homeostasis" is the best word to describe it.

Similarly, the flux through the reactions of glycolysis and gluconeogenesis is controlled by regulating the activities of certain key enzymes. Sometimes the cells make glucose and sometimes they degrade it. The reactants and products of many of the reactions are at steady-state equilibrium concentrations by virtue of the fact that the activities of the enzymes are not regulated. However, the concentrations of reactants and products of metabolically irreversible reactions can change considerably as the cells switch from gluconeogenesis to glycolysis. Or from production of pyruvate to production of ethanol or lactate.

This is regulation and it's an important concept. Homeostasis is not.

Students should be able to relate the laws of thermodynamics to homeostasis and explain how the cell or organism maintains homeostasis (a system seemingly in equilibrium) using nonequilibrium mechanisms.

It's important that students understand thermodynamics and it's important that they understand how metabolic reactions are regulated so that cells of all types can exist under many different environmental conditions where the supply of different nutrients can change dramatically.

Quantifying Homeostasis

The tendency of chemical reactions and processes to occur under homeostatic conditions in the cell is understood and quantifiable with the equation for the change in Gibbs free energy, ΔG, as based on the steady concentrations, not the equilibrium concentrations, of reactants and products. Because ΔG is a measure of amount of chemical work a process can yield, ΔG < 0 for any process that would tend to produce products in the presence of a suitable catalyst. Biological systems have evolved to harness chemical work from hundreds of reactions that occur in the cell in any given time period.

I don't agree with this fundamental concept. It's true that "ΔG < 0 for any process that would tend to produce products in the presence of a suitable catalyst" as long as you think of a "process" as a complete pathway. On the other hand, many of the individual reactions are at equilibrium so cells don't need to expend effort to maintain the standard concentrations. Cells are perfectly capable of the net synthesis of glucose, for example, even if the Gibbs free energy change of the aldolase reaction is zero. That's a fundamental concept of biochemistry that every student needs to understand. Having said that, it's true that many of the key regulated enzymes catalyze reactions that are at concentrations far from equilibrium. Changes in those concentrations determine whether the enzyme is active or not. If those concentrations were maintained at a constant steady-state (homeostasis) then the rate of the reactions would never change. Understanding regulation is the key concept, not homeostasis.

Organization of Chemical Processes

Reactions critical to living systems are organized into pathways by which key cellular metabolites are interconverted. Organization into pathways facilitates regulation required for the maintenance of homeostasis. Pathways or parts of pathways are often organized structurally as well as chemically, with pathway enzymes linked or sequestered in some manner. Pathways are sometimes separated from each other by structural compartments within cells.

I don't have much of a problem with this paragraph except that I think "homeostasis" is not the right word.

Control Mechanisms

Homeostasis within a cell or organism is regulated in many ways, for example by alterations in gene expression, covalent modifications of proteins catalyzing key steps in a pathway, allosteric regulators, the action of regulatory proteins and RNA molecules, and activation or inactivation of enzymatic catalysts by proteolytic or nucleolytic cleavage.

Students should be able to summarize the different levels of control (including reaction compartmentalization, gene expression, covalent modification of key enzymes, allosteric regulation of key enzymes, substrate availability, and proteolytic cleavage), and relate these different levels of control to homeostasis.

Control mechanisms are important. They allow cells to operate under a wide variety of different conditions with very different concentrations of some reactants and products. The concentration of lactate, for example, is very different in resting muscle cells than in muscle cells that are starved for oxygen.

I really don't see what you gain by referring to this as "homeostasis." I see what you lose.

Cellular and Organismal Homeostasis

Homeostasis in the cell is maintained by regulation, and by the more or less steady state exchange of materials and energy with its surroundings (e.g. taking in nutrients, expelling metabolic byproducts, releasing heat into the surroundings). All of these processes occur if the appropriate catalyst is present and if the net entropy of the universe increases as a result of the process (ΔS > 0), and there is an accompanying net loss of free energy (ΔG < 0). Homeostasis in an organism or colony of single celled organisms is regulated by secreted proteins and small molecules, often functioning as signals. Each chemical signal in an organism is transiently bound by specific macromolecular receptors (usually proteins), leading to an alteration in conformation, interactions with other components of one or more signaling pathways, and changes in downstream metabolic processes. Students should be able to describe homeostasis at the level of the cell, organism, or system of organisms and hypothesize how the system would react to deviations from homeostasis.

This final paragraph emphasizes that the fundamental concept is regulation. Sometimes this results in near steady-state concentrations of metabolites and sometimes it causes significant changes in those concentrations.

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Tansey, J.T., Baird, T., Cox, M.M., Fox, K.M., Knight, J., Sears, D. and Bell, E. (2013) Foundational concepts and underlying theories for majors in “biochemistry and molecular biology”. Biochem. Mol. Biol. Educ., 41:289–296. [doi: 10.1002/bmb.20727]