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7.5: Metabolism without Oxygen - Biology

7.5: Metabolism without Oxygen - Biology


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7.5: Metabolism without Oxygen

7.5: Metabolism without Oxygen - Biology

Some prokaryotes and eukaryotes use anaerobic respiration in which they can create energy for use in the absence of oxygen.

Learning Objectives

Describe the process of anaerobic cellular respiration.

Key Takeaways

Key Points

  • Anaerobic respiration is a type of respiration where oxygen is not used instead, organic or inorganic molecules are used as final electron acceptors.
  • Fermentation includes processes that use an organic molecule to regenerate NAD + from NADH.
  • Types of fermentation include lactic acid fermentation and alcohol fermentation, in which ethanol is produced.
  • All forms of fermentation except lactic acid fermentation produce gas, which plays a role in the laboratory identification of bacteria.
  • Some types of prokaryotes are facultatively anaerobic, which means that they can switch between aerobic respiration and fermentation, depending on the availability of oxygen.

Key Terms

  • archaea: A group of single-celled microorganisms. They have no cell nucleus or any other membrane-bound organelles within their cells.
  • anaerobic respiration: A form of respiration using electron acceptors other than oxygen.
  • fermentation: An anaerobic biochemical reaction. When this reaction occurs in yeast, enzymes catalyze the conversion of sugars to alcohol or acetic acid with the evolution of carbon dioxide.

Anaerobic Cellular Respiration

The production of energy requires oxygen. The electron transport chain, where the majority of ATP is formed, requires a large input of oxygen. However, many organisms have developed strategies to carry out metabolism without oxygen, or can switch from aerobic to anaerobic cell respiration when oxygen is scarce.

During cellular respiration, some living systems use an organic molecule as the final electron acceptor. Processes that use an organic molecule to regenerate NAD + from NADH are collectively referred to as fermentation. In contrast, some living systems use an inorganic molecule as a final electron acceptor. Both methods are called anaerobic cellular respiration, where organisms convert energy for their use in the absence of oxygen.

Certain prokaryotes, including some species of bacteria and archaea, use anaerobic respiration. For example, the group of archaea called methanogens reduces carbon dioxide to methane to oxidize NADH. These microorganisms are found in soil and in the digestive tracts of ruminants, such as cows and sheep. Similarly, sulfate-reducing bacteria and archaea, most of which are anaerobic, reduce sulfate to hydrogen sulfide to regenerate NAD + from NADH.

Anaerobic bacteria: The green color seen in these coastal waters is from an eruption of hydrogen sulfide-producing bacteria. These anaerobic, sulfate-reducing bacteria release hydrogen sulfide gas as they decompose algae in the water.

Eukaryotes can also undergo anaerobic respiration. Some examples include alcohol fermentation in yeast and lactic acid fermentation in mammals.

Lactic Acid Fermentation

The fermentation method used by animals and certain bacteria (like those in yogurt) is called lactic acid fermentation. This type of fermentation is used routinely in mammalian red blood cells and in skeletal muscle that has an insufficient oxygen supply to allow aerobic respiration to continue (that is, in muscles used to the point of fatigue). The excess amount of lactate in those muscles is what causes the burning sensation in your legs while running. This pain is a signal to rest the overworked muscles so they can recover. In these muscles, lactic acid accumulation must be removed by the blood circulation and the lactate brought to the liver for further metabolism. The chemical reactions of lactic acid fermentation are the following:

Pyruvic acid + NADH ↔ lactic acid + NAD +

Lactic acid fermentation: Lactic acid fermentation is common in muscle cells that have run out of oxygen.

The enzyme used in this reaction is lactate dehydrogenase (LDH). The reaction can proceed in either direction, but the reaction from left to right is inhibited by acidic conditions. Such lactic acid accumulation was once believed to cause muscle stiffness, fatigue, and soreness, although more recent research disputes this hypothesis. Once the lactic acid has been removed from the muscle and circulated to the liver, it can be reconverted into pyruvic acid and further catabolized for energy.

Alcohol Fermentation

Another familiar fermentation process is alcohol fermentation, which produces ethanol, an alcohol. The use of alcohol fermentation can be traced back in history for thousands of years. The chemical reactions of alcoholic fermentation are the following (Note: CO2 does not participate in the second reaction):

Pyruvic acid → CO2 + acetaldehyde + NADH → ethanol + NAD +

Alcohol Fermentation: Fermentation of grape juice into wine produces CO2 as a byproduct. Fermentation tanks have valves so that the pressure inside the tanks created by the carbon dioxide produced can be released.

The first reaction is catalyzed by pyruvate decarboxylase, a cytoplasmic enzyme, with a coenzyme of thiamine pyrophosphate (TPP, derived from vitamin B1 and also called thiamine). A carboxyl group is removed from pyruvic acid, releasing carbon dioxide as a gas. The loss of carbon dioxide reduces the size of the molecule by one carbon, making acetaldehyde. The second reaction is catalyzed by alcohol dehydrogenase to oxidize NADH to NAD + and reduce acetaldehyde to ethanol.

The fermentation of pyruvic acid by yeast produces the ethanol found in alcoholic beverages. Ethanol tolerance of yeast is variable, ranging from about 5 percent to 21 percent, depending on the yeast strain and environmental conditions.

Other Types of Fermentation

Various methods of fermentation are used by assorted organisms to ensure an adequate supply of NAD + for the sixth step in glycolysis. Without these pathways, that step would not occur and no ATP would be harvested from the breakdown of glucose.Other fermentation methods also occur in bacteria. Many prokaryotes are facultatively anaerobic. This means that they can switch between aerobic respiration and fermentation, depending on the availability of oxygen. Certain prokaryotes, like Clostridia, are obligate anaerobes. Obligate anaerobes live and grow in the absence of molecular oxygen. Oxygen is a poison to these microorganisms, killing them on exposure.

It should be noted that all forms of fermentation, except lactic acid fermentation, produce gas. The production of particular types of gas is used as an indicator of the fermentation of specific carbohydrates, which plays a role in the laboratory identification of the bacteria.


Anaerobic Cellular Respiration

Certain prokaryotes, including some species of bacteria and Archaea, use anaerobic respiration. For example, the group of Archaea called methanogens reduces carbon dioxide to methane to oxidize NADH. These microorganisms are found in soil and in the digestive tracts of ruminants, such as cows and sheep. Similarly, sulfate-reducing bacteria and Archaea, most of which are anaerobic (Figure 1), reduce sulfate to hydrogen sulfide to regenerate NAD + from NADH.


Human Organ Systems

Functionally related organs often cooperate to form whole organ systems. The 12 diagrams in Figure 7.5.3 show 11 human organ systems, including separate diagrams for the male and female reproductive systems. Some of the organs and functions of the organ systems are identified. Each system is also described in more detail in the text that follows. Most of these human organ systems are also the subject of separate chapters in this book.

Figure 7.5.3 Human Organ Systems. These diagrams represent 11 human organ systems and show some of their organs and functions. The male and female reproductive systems are shown separately because of their significant differences.

Organs of the integumentary system include the skin, hair, and nails. The skin is the largest organ in the body. It encloses and protects the body and is the site of many sensory receptors. The skin is the body’s first defense against pathogens, and it also helps regulate body temperature and eliminate wastes in sweat.


Oxygen and mammalian cell culture: are we repeating the experiment of Dr. Ox?

Mammalian cell culture represents a cornerstone of modern biomedical research. There is growing appreciation that the media conditions in which cells are cultured can profoundly influence the observed biology and reproducibility. Here, we consider a key but often ignored variable, oxygen, and review why being mindful of this environmental parameter is so important in the design and interpretation of cell culture studies.

In his 1872 short story ‘Doctor Ox’s Experiment’, Jules Verne describes a sleepy Flemish town that is turned on its head by a rogue scientist, Dr. Ox, who is obsessed with oxygen. Bent on testing the effects of high oxygen on living beings, Dr. Ox proceeds to flood the town’s atmosphere with pure oxygen under the pretence of modernizing the town’s lighting system. The results of Dr. Ox’s experiment are immediately apparent: oxygen ‘animates’ the previously tranquil townspeople, who become manic, excitable and ravenous plants grow to monstrous proportions and animals become aggressive. Although Dr. Ox would have let the experiment continue indefinitely, a fiery explosion at the oxygen factory brings everything to an end. The town returns to its serene existence, none the wiser. But what can we, as experimental biologists, learn from this fictional piece?


Evolutionary Significance of Obligate Anaerobes

The existence of obligate anaerobes is a significant clue in the theory of the origins of life on planet Earth. While our atmosphere has a significant amount of oxygen now, that may not have always been the case. The presence of obligate anaerobes today suggests that the atmosphere once had much less oxygen, allowing bacteria to survive without oxygen facilitating enzymes. The theory suggests that with the rise of photosynthetic organisms, there also came a rise in the level of oxygen in the environment.


Reviewers' comments

Reviewer 1: Dr. Eric Bapteste

In my view this article can be accepted for publication in Biology Direct. I would nonetheless appreciate if the authors would attempt some further investigations regarding the origin(s) of the transferred STC genes.

In particular, I would be curious to know more about the possible mechanisms involved in these transfers. How was the first STC gene acquired by eukaryotes if this gene is required for phagocytosis? It could not be through predation then. Were the first eukaryotes who acquired this gene non phagocytic ones, or did this gene come to replace another (non orthologous) gene fulfilling this function? For the more recent STC gene acquisitions: is there any evidence in the sequences from known (eukaryotic) viruses that the STC gene may have been mobilized by viruses? Would it be possible to check in (some of) the eukaryotic genomes owning the STC gene whether some traces of transposon activity can be found next to the acquired STC gene? Is there a distant homologue of the STC gene in the mitochondria: could this gene have been transferred internally from that symbiont, or using that symbiont as an 'entry door' into the eukaryotic cell?

Authors' response: Considering the fact that the sterol biosynthesis pathway is broadly distributed across phylogenetically divergent eukaryotes, it is very likely that the common ancestor of extant eukaryotes already possessed this metabolic pathway (see references [3] and [23]). Thus, it is reasonable to assume, as we do, that the first (putative aerobic or facultatively anaerobic) eukaryote that acquired the STC gene from a bacterium was a normal sterol-producing phagocytic eukaryote. The acquisition of the STC gene is thought to be one of strategies for secondary adaptation to living exclusively in oxygen-poor environments. Similarly, the hosts for the subsequent eukaryote-to-eukaryote transfers of the STC genes we propose would also originally be able to synthesize sterols and perform phagocytosis/endocytosis. But once they acquired the STC gene, they could easily adapt to living permanently in anoxic/hypoxic environments. The detailed mechanisms mediating the lateral gene transfers (LGTs) that we describe, as with many proposed LGTs in eukaryotic genomes, remain unclear. We could not find any traces of putative LGT vectors such as transposable elements in the flanking regions of the STC genes in the genomes from the ciliates Tetrahymena and Paramecium. Furthermore, since the other STC genes found in this study were retrieved from EST data, their non-transcribed genomic flanking regions remain uncharacterized at this time. Finally, as far as we know, there is no distantly-related STC homologue encoded in any mitochondrial genome characterized to date. Thus, there is no evidence linking our findings to endosymbiotic gene transfer from the mitochondrial (or plastid) ancestor and no other reason to think these organelles are relevant to this case of gene transfer.

I also wonder what is the general 'availability' of the STC genes in the environment. Are there STC genes everywhere (which would enhance the chance of some needy eukaryotes to pick them anywhere), or is their distribution somehow restricted to some environments (in which we could then imagine that the transfer had more chances to occur)? It would be interesting to see what the general distribution of this gene is based on sequences in publicly available metagenomic datasets.

Authors' response: This is an interesting point. We did investigate this, however, the STC gene could not be found in publicly available metagenomic datasets including anoxic/hypoxic ones. Such absence of this 'eukaryotic' gene is probably due to the overwhelming dominance of prokaryotic sequences in the metagenomic datasets. It is currently impossible to rigorously address the issue the reviewer has raised. However, metagenomic sequencing efforts that are targeted at eukaryotic microbes specifically may allow us to address this in future.

Finally, the very last section of the paper could be slightly toned-down. I would prefer that the authors suggest that their 'findings MAY (my suggestion) have important implications for the field of geochemistry' rather than their 'findings have important implications for the field of geochemistry'.

Authors' response: Indeed, we were perhaps too enthusiastic in this section. Accordingly we have taken the reviewer's advice.

Reviewer 2: Dr. Eugene V. Koonin

This is an excellent study that solves a real biological puzzle: how anaerobic eukaryotes do without sterols and in particular how do they manage to perform phagocytosis? It is particularly impressive that, after coming up with the hypothesis that tetrahymanol is the functional analog of sterols in these organisms, on the basis of genome and EST sequence analysis, the authors actually discover this molecule directly. The phylogenetic analysis presented in the paper is compelling. It is an important addition to the existing understanding of the evolution of eukaryotes. There is nothing to criticize.

Authors' response: We thank the reviewer for his kind comments.


Discussion

In this paper we have shown – both theoretically and experimentally – how it is possible to kill a pathogen selectively, with minimal effect on the host, by targeting a metabolic pathway that is essential for host and pathogen alike. Although targeting a unique pathogen protein may open powerful avenues for selective inhibition, uniqueness itself does not make it a potent drug target against the pathogen. A drug against a target that is not essential for survival of the pathogen will not kill it. Furthermore, if near-complete inhibition of the unique target would be needed in order to kill the pathogen, the required inhibitor dosage would increase the risk of off-target side-effects to the host. Essentiality of the target pathway and relatively high flux control of the specific target in the parasite thus need to be the first criteria for potential targets. Identification of a pathogen-specific target that meets these criteria enables design of drugs with strong molecular selectivity.

Our study shows that very promising targets can exist outside the realm of the unique proteins. Glycolysis is an essential pathway for bloodstream-form Trypanosoma brucei and a moderate inhibition (50%) is sufficient to kill the parasite 12 . This makes it a promising target pathway for antitrypanosomal drugs. However, T. brucei glycolysis does not contain unique parasitic proteins (although some are evolutionary and structurally distant from their human counterparts (see ref. 13 and references therein). Moreover, glycolysis is also essential for many human cell types. We have demonstrated that this need not be an obstacle: quantitative differences between trypanosome and erythrocyte lead to strong network-based selectivity. This network-based selectivity depends equally on the flux control exerted by the target enzyme and on the in vivo elasticity (sensitivity) of the target enzyme towards the drug. The latter depends on the degree of saturation of the enzyme with its substrates and products. The generality of this principle makes it applicable to any disease in which specific cell types must be targeted selectively. We have further shown that this network-based selectivity is just as important as selectivity based on the structure of the molecular target (Eq. 7).

Here we validated model simulations for the network-selectivity of glucose transport inhibition towards T. brucei over erythrocytes. We also showed that inhibition of pyruvate kinase is indeed detrimental to erythrocytes, as predicted by the corresponding model. With respect to some other targets, both kinetic models had previously been validated extensively. For the T. brucei model, apart from the glucose transporter itself 19 , the effect of reduction of various other enzyme activities had been validated by RNAi knockdowns 9 . The erythrocyte model has been validated by comparing predictions to clinical data of inborn enzyme deficiencies 36 .

Drug design that is mechanistic and structure-based will often lead to the development of competitive inhibitors. Several drugs in clinical use are competitive enzyme inhibitors, such as the phosphodiesterase inhibitor Viagra and the bcl-abl kinase inhibitor Gleevec 17 . This was why we focused on competitive inhibitors first. The values observed for the elasticity coefficients suggest, however, that other modes of drug action may lead to a different network-based selectivity. For instance, in the computer models a competitive inhibitor of aldolase was calculated to be somewhat selective against erythrocytes (Supplementary Fig. S1) due to a lower concentration of the competing substrate fructose-1,6-bisphosphate (0.0010 mM in erythrocytes versus 13 mM in trypanosomes). This caused a higher elasticity in the erythrocyte ( was 𢄦.7 ×� 𢄢 in erythrocytes versus 𢄣.0뜐 𢄣 in trypanosomes), conferring a 22-fold selectivity towards the erythrocyte enzyme. Since uncompetitive inhibitors become more effective at higher substrate concentrations 7 , uncompetitive inhibitors of aldolase should be selective against trypanosomes, which we confirmed computationally (Supplementary Fig. S4).

Each host cell type has its own characteristic metabolic network. Indeed, our in vitro tests on primary neurons and liver cells show that these cell types are more affected by glucose transport inhibition than erythrocytes, but still markedly less than trypanosomes. With respect to toxicity for these cells it may therefore be useful to enhance the network selectivity with molecular selectivity. Molecular side-effects against the hepatocyte and brain transporters GLUT2 and GLUT3, respectively, should then be more important to consider than those against the erythrocyte transporter GLUT1. In addition, a chronic and severe deficiency of GLUT1 is known to affect the brain, since this transporter is also essential for glucose uptake through the blood-brain barrier 37 , suggesting that a combined network- and structure-based approach will also for GLUT1 be the most effective. Realistically, however, a more comprehensive analysis of different host cell types will be needed. Although such an endeavor may be challenging, it is warranted by the fact that glycolysis is a promising target not only in trypanosomes, but also in various parasites including Plasmodium, as well as in certain tumors. Along these lines, we showed that glucose transport inhibition strongly affected metabolism in Plasmodium-infected erythrocytes. A characterization of host-cell network sensitivity can be reused for all these applications. In this light our results should be viewed as proof of principle that network selectivity is possible. Where necessary and possible, selectivity may be increased by exploiting structural differences between pathogen and host targets, eliciting synergy between network- and structure-based selectivity (cf. Eq. 7). The results obtained with compound 3361, which was selected for absence of an effect against the erythrocyte glucose transporter GLUT1 29 , suggest that the latter is feasible. This development may well be boosted by the elucidation of the crystal structure of GLUT1 38 .

A strong advantage of the selection of drug targets from a pathway operating in both pathogen and host is that it allows compound re-purposing. For instance, anticancer compounds that were discarded because of their limited effect on tumors, can now be re-tested for an effect on the high-ranking enzymes within trypanosome glycolysis ( Fig. 1d ).

The same approach will be crucial for identifying selective drug targets for the treatment of certain types of cancer. Since cancer cells originate from their host, their genome only encodes pathways that also operate in healthy cells. Upregulated and altered metabolism has been re-recognized as a hallmark of cancer and is back in focus as a target for anticancer drugs 39 . Differences in gene expression levels between tumor cells and healthy cells may be exploited to optimize network-based selectivity. We recommend that the strategy described in this paper be implemented in the development of potent drugs that cause minimal collateral damage to host tissues.


Anaerobic Metabolism

Unlike the form explained above, anaerobic metabolism does not require the presence of oxygen to convert raw materials into energy. However, anaerobic glycolysis is far less efficient, producing only two molecules of ATP, in comparison to aerobic metabolism&rsquos impressive 34.

The body relies on anaerobic respiration when a sudden burst of energy is required in a short amount of time. For example, imagine that you are a sprinter or a weightlifter your physical demands are usually intense, but only for a limited amount of time. Since aerobic metabolism takes more time, the body uses anaerobic metabolism to generate energy for immediate use from carbohydrates, but not fat or protein. Beginning with a single molecule of glucose, the glycolysis process unfolds in the cytoplasm of a cell, and does not require any organelles.

Additionally, for activities such as sprinting or weightlifting, the body is in short supply of oxygen. The heart is pumping blood as fast as it can, but not enough and not in time to satisfy the needs of the muscles or other cells.

(Photo Credit: YassineMrabet/Wikimedia Commons)

Unfortunately, one of the byproducts of anaerobic metabolism is lactic acid, which can cause fatigue. A rapid buildup of lactic acid is what causes cramps in athletes who push themselves too hard without properly warming up &ndash or when the body fails to balance aerobic and anaerobic metabolism.

The body&rsquos default is aerobic metabolism since it is so much more efficient than anaerobic (unless you are an anaerobic bacteria, then oxygen could kill you). Anaerobic respiration is there in case of emergency situations until the body can get back to its original oxygen dependent self.


INACTIVATION OF NADPH-CYTOCHROME P-450 () REDUCTASE BY 2,3-BUTANEDIONE AND PHENYLGLYOXAL. EVIDENCE FOR AN ESSENTIAL ARGININE

I INTRODUCTION

The hepatic microsomal monooxygenase system is composed of two enzymes, a hemeprotein, cytochrome P-450, and a flavoprotein, NADPH-cytochrome P-450 reductase. NADPH-cytochrome P-450 reductase catalyzes the transfer of electrons from NADPH to the hemin iron of cytochrome P-450 as well as to a number of other electron acceptors such as cytochrome c and 2,6-dichlorophenolindophenol. Although it has been firmly established that the reductase contains one mole each of FAD and FMN ( 1–3 ), very little is known about the active site domain of this enzyme. Several studies have implicated the importance of cysteine residues. However, only two have presented evidence that at least one cysteine residue is at or near the NADPH binding site ( 4 , 5 ). The sensitivity of the reductase to 2,3-butanedione and phenylglyoxal which are commonly used to modify arginine residues in proteins ( 6 ) suggests that there is also an arginine residue at the active site of this enzyme.


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