Product inhibition

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Product inhibition is a type of enzyme inhibition where the product of an enzyme reaction inhibits its production. [1] Cells utilize product inhibition to regulate of metabolism as a form of negative feedback controlling metabolic pathways. [2] Product inhibition is also an important topic in biotechnology, as overcoming this effect can increase the yield of a product, such as an antibiotic. [3] Product inhibition can be competitive, non-competitive or uncompetitive.

Contents

Mitigation of product inhibition

Reactor design

One method to reduce product inhibition is the use of a membrane reactor. [4] These bioreactors uses a membrane to separate products from the rest of the reactor, limiting their inhibition. If the product differs greatly in size from the cells producing it, and the substrate feeding the cells, then the reactor can utilize a semipermeable membrane allowing to products to exit the reactor while leaving the cells and substrate behind to continue reacting making more product. Other reactor systems use chemical potential to separate products from the reactor, such as solubility of different compounds allowing one to pass through the membrane. Electrokinetic bioreactor systems have been developed which use electrolysis, a process that uses electrical charge to remove the product from the bioreactor system. [5]

External loop reactor uses current created by air bubbles flowing through the reactor to create a flow that brings the reactor contents through an external loop. A separating membrane can be placed in the external loop to collect product, and reduce product inhibition. A downside to external loop reactors is they create additional shear stress. [6] Submerged membrane bioreactors have the membrane contained within the main chamber of the bioreactor. [6]

A separative bioreactor is a type of continuous reactor where the producing cells are mounted on a resin membrane as to not flow out of the reactor as substrate is passed over them. The continuous flow of the reactor takes the product downstream as it is produced. [7]

Other methods of mitigating product inhibition

Integratedliquid-liquid extraction can be used to remove products that have a density that differs from the rest of the bioreactors contents. [8] This is done by adding a solvent downstream of the bioreactor and letting the product separate out in a settling tank before the bioreactor effluent is moved to a secondary reactor or returned to its initial reactor to continue its cultivation. This process can be done in batch or continuous operation.

Vacuum extraction [9] can be used in fermentation to remove ethanol from a reactor. When the liquid in the vessel is placed in vacuum conditions the ethanol begins to evaporate because its more volatile than the rest of the reactor contents. This technique requires an acclimation period for the yeast in the reactor to adapt to the lower pressure environment.[ citation needed ]

Product neutralization if a products inhibition due to its pH then it can be neutralized in the reactor and further processed downstream back into its original form.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Enzyme</span> Large biological molecule that acts as a catalyst

Enzymes are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Lactic acid fermentation</span> Series of interconnected biochemical reactions

Lactic acid fermentation is a metabolic process by which glucose or other six-carbon sugars are converted into cellular energy and the metabolite lactate, which is lactic acid in solution. It is an anaerobic fermentation reaction that occurs in some bacteria and animal cells, such as muscle cells.

<span class="mw-page-title-main">Bioreactor</span> System that supports a biologically active environment

A bioreactor refers to any manufactured device or system that supports a biologically active environment. In one case, a bioreactor is a vessel in which a chemical process is carried out which involves organisms or biochemically active substances derived from such organisms. This process can either be aerobic or anaerobic. These bioreactors are commonly cylindrical, ranging in size from litres to cubic metres, and are often made of stainless steel. It may also refer to a device or system designed to grow cells or tissues in the context of cell culture. These devices are being developed for use in tissue engineering or biochemical/bioprocess engineering.

Industrial fermentation is the intentional use of fermentation in manufacturing processes. In addition to the mass production of fermented foods and drinks, industrial fermentation has widespread applications in chemical industry. Commodity chemicals, such as acetic acid, citric acid, and ethanol are made by fermentation. Moreover, nearly all commercially produced industrial enzymes, such as lipase, invertase and rennet, are made by fermentation with genetically modified microbes. In some cases, production of biomass itself is the objective, as is the case for single-cell proteins, baker's yeast, and starter cultures for lactic acid bacteria used in cheesemaking.

<span class="mw-page-title-main">Lactic acid bacteria</span> Order of bacteria

Lactobacillales are an order of gram-positive, low-GC, acid-tolerant, generally nonsporulating, nonrespiring, either rod-shaped (bacilli) or spherical (cocci) bacteria that share common metabolic and physiological characteristics. These bacteria, usually found in decomposing plants and milk products, produce lactic acid as the major metabolic end product of carbohydrate fermentation, giving them the common name lactic acid bacteria (LAB).

Uncompetitive inhibition is a type of inhibition in which the apparent values of the Michaelis–Menten parameters and are decreased in the same proportion.

<span class="mw-page-title-main">Mixed acid fermentation</span> Biochemical conversion of six-carbon sugars into acids in bacteria

In biochemistry, mixed acid fermentation is the metabolic process by which a six-carbon sugar is converted into a complex and variable mixture of acids. It is an anaerobic (non-oxygen-requiring) fermentation reaction that is common in bacteria. It is characteristic for members of the Enterobacteriaceae, a large family of Gram-negative bacteria that includes E. coli.

<span class="mw-page-title-main">Fermentation</span> Metabolic process producing energy in the absence of oxygen

Fermentation is a metabolic process that produces chemical changes in organic substances through the action of enzymes. In biochemistry, it is broadly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food production, it may more broadly refer to any process in which the activity of microorganisms brings about a desirable change to a foodstuff or beverage. The science of fermentation is known as zymology.

<span class="mw-page-title-main">Membrane reactor</span>

A membrane reactor is a physical device that combines a chemical conversion process with a membrane separation process to add reactants or remove products of the reaction.

The Pasteur effect describes how available oxygen inhibits ethanol fermentation, driving yeast to switch toward aerobic respiration for increased generation of the energy carrier adenosine triphosphate (ATP). More generally, in the medical literature, the Pasteur effect refers to how the cellular presence of oxygen causes in cells a decrease in the rate of glycolysis and also a suppression of lactate accumulation. The effect occurs in animal tissues, as well as in microorganisms belonging to the fungal kingdom.

Fed-batch culture is, in the broadest sense, defined as an operational technique in biotechnological processes where one or more nutrients (substrates) are fed (supplied) to the bioreactor during cultivation and in which the product(s) remain in the bioreactor until the end of the run. An alternative description of the method is that of a culture in which "a base medium supports initial cell culture and a feed medium is added to prevent nutrient depletion". It is also a type of semi-batch culture. In some cases, all the nutrients are fed into the bioreactor. The advantage of the fed-batch culture is that one can control concentration of fed-substrate in the culture liquid at arbitrarily desired levels.

<span class="mw-page-title-main">Acetone–butanol–ethanol fermentation</span> Chemical process

Acetone–butanol–ethanol (ABE) fermentation, also known as the Weizmann process, is a process that uses bacterial fermentation to produce acetone, n-butanol, and ethanol from carbohydrates such as starch and glucose. It was developed by chemist Chaim Weizmann and was the primary process used to produce acetone, which was needed to make cordite, a substance essential for the British war industry during World War I.

Syngas fermentation, also known as synthesis gas fermentation, is a microbial process. In this process, a mixture of hydrogen, carbon monoxide, and carbon dioxide, known as syngas, is used as carbon and energy sources, and then converted into fuel and chemicals by microorganisms.

Membrane bioreactors are combinations of some membrane processes like microfiltration or ultrafiltration with a biological wastewater treatment process, the activated sludge process. These technologies are now widely used for municipal and industrial wastewater treatment. The two basic membrane bioreactor configurations are the submerged membrane bioreactor and the side stream membrane bioreactor. In the submerged configuration, the membrane is located inside the biological reactor and submerged in the wastewater, while in a side stream membrane bioreactor, the membrane is located outside the reactor as an additional step after biological treatment.

<span class="mw-page-title-main">Photofermentation</span>

Photofermentation is the fermentative conversion of organic substrate to biohydrogen manifested by a diverse group of photosynthetic bacteria by a series of biochemical reactions involving three steps similar to anaerobic conversion. Photofermentation differs from dark fermentation because it only proceeds in the presence of light.

Perstraction is a membrane extraction process, where two liquid phases are contacted across a membrane. The desired species in the feed (solute), selectively crosses the membrane into the extracting solution. Perstraction was originally developed to overcome the downsides of liquid–liquid extraction, for example extractant toxicity and emulsion formation. Perstraction has been applied to many fields including fermentation, waste water treatment and alcohol-free beverage production.

Industrial enzymes are enzymes that are commercially used in a variety of industries such as pharmaceuticals, chemical production, biofuels, food & beverage, and consumer products. Due to advancements in recent years, biocatalysis through isolated enzymes is considered more economical than use of whole cells. Enzymes may be used as a unit operation within a process to generate a desired product, or may be the product of interest. Industrial biological catalysis through enzymes has experienced rapid growth in recent years due to their ability to operate at mild conditions, and exceptional chiral and positional specificity, things that traditional chemical processes lack. Isolated enzymes are typically used in hydrolytic and isomerization reactions. Whole cells are typically used when a reaction requires a co-factor. Although co-factors may be generated in vitro, it is typically more cost-effective to use metabolically active cells.

Substrate inhibition in bioreactors occurs when the concentration of substrate exceeds the optimal parameters and reduces the growth rate of the cells within the bioreactor. This is often confused with substrate limitation, which describes environments in which cell growth is limited due to of low substrate. Limited conditions can be modeled with the Monod equation; however, the Monod equation is no longer suitable in substrate inhibiting conditions. A Monod deviation, such as the Haldane (Andrew) equation, is more suitable for substrate inhibiting conditions. These cell growth models are analogous to equations that describe enzyme kinetics, although, unlike enzyme kinetics parameters, cell growth parameters are generally empirically estimated.

References

  1. ↑ Walter, Charles; Frieden, Earl (1963). "The Prevalence and Significance of the Product Inhibition of Enzymes". In Nord, F.F. (ed.). Advances in Enzymology and Related Subjects of Biochemistry. Vol. 25. pp. 167–274. doi:10.1002/9780470122709.ch4. ISBN   978-0-470-12270-9. PMID   14149677.
  2. ↑ Hutson, NJ; Kerbey, AL; Randle, PJ; Sugden, PH (1979). "Regulation of pyruvate dehydrogenase by insulin action". Progress in Clinical and Biological Research. 31: 707–719. PMID   231784. NAID   10010916605.
  3. ↑ Schügerl, Karl; Hubbuch, Jürgen (June 2005). "Integrated bioprocesses". Current Opinion in Microbiology. 8 (3): 294–300. doi:10.1016/j.mib.2005.01.002. PMID   15939352.
  4. ↑ Fan, Rong; Ebrahimi, Mehrdad; Czermak, Peter (3 May 2017). "Anaerobic Membrane Bioreactor for Continuous Lactic Acid Fermentation". Membranes. 7 (2): 26. doi: 10.3390/membranes7020026 . PMC   5489860 . PMID   28467384.
  5. ↑ Li, Hong; Mustacchi, Roberta; Knowles, Christopher J; Skibar, Wolfgang; Sunderland, Garry; Dalrymple, Ian; Jackman, Simon A (January 2004). "An electrokinetic bioreactor: using direct electric current for enhanced lactic acid fermentation and product recovery". Tetrahedron. 60 (3): 655–661. doi:10.1016/j.tet.2003.10.110.
  6. 1 2 Carstensen, Frederike; Apel, Andreas; Wessling, Matthias (March 2012). "In situ product recovery: Submerged membranes vs. external loop membranes". Journal of Membrane Science. 394–395: 1–36. doi:10.1016/j.memsci.2011.11.029.
  7. ↑ Arora, M. B.; Hestekin, J. A.; Snyder, S. W.; St. Martin, E. J.; Lin, Y. J.; Donnelly, M. I.; Millard, C. Sanville (July 2007). "The Separative Bioreactor: A Continuous Separation Process for the Simultaneous Production and Direct Capture of Organic Acids". Separation Science and Technology. 42 (11): 2519–2538. doi:10.1080/01496390701477238. PMC   3662075 . PMID   23723533.
  8. ↑ Kaur, Guneet; Srivastava, A.K.; Chand, Subhash (December 2015). "Debottlenecking product inhibition in 1,3-propanediol fermentation by In-Situ Product Recovery". Bioresource Technology. 197: 451–457. doi:10.1016/j.biortech.2015.08.101. PMID   26356117.
  9. ↑ Tavares, Bruna; Felipe, Maria das Graças de Almeida; dos Santos, Júlio César; Pereira, Félix Monteiro; Gomes, Simone Damasceno; Sene, Luciane (February 2019). "An experimental and modeling approach for ethanol production by Kluyveromyces marxianus in stirred tank bioreactor using vacuum extraction as a strategy to overcome product inhibition". Renewable Energy. 131: 261–267. doi:10.1016/j.renene.2018.07.030.
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