Metabolite damage

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Under metabolites damage refers to damage caused to metabolites. Metabolite damage can occur through side reactions of enzymes or spontaneous chemical reactions . Many metabolites are chemically reactive and unstable and can react with other cellular components or be otherwise chemically converted.

Types of damage

Similar to DNA and proteins , metabolites are also susceptible to undesired side reactions, the reaction products of which are known as damage. Damage can occur chemically or enzymatically through enzymatic side reactions. While DNA and protein damage are relatively well researched, metabolite damage is a new area of ​​research. This is due, among other things, to the high diversity and number of reactive (and thus damage-prone) metabolites.

Chemical damage

Examples of spontaneous chemical reactions that can happen to a metabolite in vivo.

Many metabolites are chemically reactive and unstable and therefore more susceptible to chemical damage. In general, any chemical reaction that takes place outside a living organism ( in vitro ) under physiological conditions can also take place in a living organism ( in vivo ). Typical types of chemical damage to metabolites that can occur in the cell are racemization , rearrangement , elimination , photolysis , addition and condensation .

Some metabolites are so reactive that their half-life is measured in minutes. For example, 1,3-bisphosphoglycerate , an intermediate in glycolysis , has a half-life of 27 minutes in vivo .

Enzymatic damage

Although enzymes generally have a high substrate specificity, side reactions of enzymes can lead to unusable and in some cases toxic products. While the reaction rates of these side reactions are much slower than those of the metabolic reactions, the accumulation of damaged metabolites (by-products) over time can be significant. For example, mitochondrial malate dehydrogenase reduces the substrate α-ketoglutaric acid to L-2-hydroxyglutarate 10 7 times more slowly than the actual substrate oxaloacetate . L-2-hydroxyglutarate can still be several grams per day in adult humans.

Damage control systems

Damaged metabolites (due to enzymatic or chemical damage) have a different, usually less beneficial use in the cell and are often toxic. To avoid cellular poisoning that can occur from the accumulation of damaged metabolites, organisms have developed mechanisms. These damage control systems can include one or more specific enzymes. Damage to macromolecules due to spontaneous reactions or enzymatic errors can be repaired by enzymatic control systems. The same principle applies to metabolites that are susceptible to damage from spontaneous chemical reactions or enzymatic errors. Metabolite damage control systems can either repair the damage directly (repair) or prevent it (prevention). A directed overflow is a special case of prevention. There are three categories of damage control systems:

a) Repair on DNA or proteins. b) Metabolite damage: Damage reactions are indicated by red arrows, and damage control systems by blue arrows. The black arrow at the very bottom describes normal enzymatic reactions, and the dashed black arrow slow, spontaneous reactions.

Repair of damaged metabolites

Repair involves converting damaged metabolites back to their original states. The concept is similar to DNA repair . For example, malate dehydrogenase reduces α-ketoglutarate to L-2-hydroxyglutarate in a side reaction . This product represents a dead end in the metabolism and is not a substrate for other enzymes in the central metabolism . An accumulation of L-2-hydroxyglutarate also leads to L-2-hydroxyglutaric aciduria , a metabolic disease . The repair enzyme α-hydroxyglutarate dehydrogenase oxidizes L-2-hydroxyglutarate back to α-ketoglutarate, and thus repairs the metabolite.

Prevention of metabolite damage

Prevention prevents future damage before it can happen. A distinction is made between two mechanisms in prevention: on the one hand, reactive metabolites can be converted into less harmful metabolites, or physiological but slow reactions are accelerated enzymatically. The reactive metabolites can either be by-products or normal but highly reactive intermediate stages in the central metabolism.

A side reaction of Rubisco example, results in small amounts of xylulose-1,5-bisphosphate comprising the Rubisco activity inhibited . The enzyme CbbY dephosphorylates xylulose-1,5-bisphosphate to the natural metabolite xylulose-5-phosphate , and thus prevents the inhibition of Rubisco activity.

Articulated overflow

The directed overflow is a special case of prevention in which an excess of physiological but reactive metabolites can lead to toxic products. Preventing this excess is therefore preemption from potential damage.

The first two intermediate products in the biosynthesis of riboflavin are extremely reactive and can spontaneously break down to 5-phosphoribosylamine and Maillard reaction products, which in turn are highly reactive and harmful. The enzyme COG3236 splits these first two intermediate products into less harmful products and thus prevents possible damage that could otherwise occur.

Metabolite Damage and Diseases

L-2-Hydroxyglutaric aciduria was the first human disease to be associated with a lack of metabolite repair enzyme. A mutation in the L2HGDH gene leads to the accumulation of α-hydroxyglutarate, which is structurally similar to glutamate and α-ketoglutarate, and thus probably inhibits other enzymes and transporters.

Systems biology

Modeling in systems biology aims to reproduce cellular metabolism in silico . Metabolite damage and its repair consume a portion of the cellular energy capacity and must therefore be incorporated into these models in order to better guide “metabolic engineering” projects.

In addition, metabolites can encode repair enzymes for many of the unknown, conserved genes found in all organisms sequenced to date.

Synthetic Biology / "Metabolic Engineering"

When constructing metabolic pathways in organisms, but also when a native metabolic pathway is massively upregulated ("metabolic engineering"), reactive metabolic intermediates can arise and negatively affect the host organism because the relevant repair pathway is missing or its flow rate is not adjusted. The construction of damage control systems can therefore be necessary in synthetic biology and in “metabolic engineering”.

Individual evidence

  1. ^ AG Golubev: [The other side of metabolism] . In: Biokhimija (Moscow, Russia) . tape 61 , no. 11 , 1996, ISSN  0320-9725 , p. 2018-2039 , PMID 9004862 .
  2. ^ Markus A. Keller, Gabriel Piedrafita, Markus Ralser: The widespread role of non-enzymatic reactions in cellular metabolism . In: Current Opinion in Biotechnology . tape 34 , 2015, ISSN  1879-0429 , p. 153–161 , doi : 10.1016 / j.copbio.2014.12.020 , PMID 25617827 , PMC 4728180 (free full text).
  3. ↑ Erwin Negelein: [36] Synthesis, determination, analysis, and properties of 1,3-diphosphoglyceric acid . tape 3 . Academic Press, January 1, 1957, pp. 216–220 ( sciencedirect.com [accessed September 23, 2016]).
  4. ↑ a b c E. Van Schaftingen, R. Rzem, M. Veiga-da-Cunha: L-2-Hydroxyglutaric aciduria, a disorder of metabolite repair . In: Journal of Inherited Metabolic Disease . tape 32 , no. 2 , 2009, ISSN  1573-2665 , p. 135-142 , doi : 10.1007 / s10545-008-1042-3 , PMID 19020988 .
  5. ^ A b c Carole L. Linster, Emile Van Schaftingen, Andrew D. Hanson: Metabolite damage and its repair or pre-emption . In: Nature Chemical Biology . tape 9 , no. 2 , 2013, ISSN  1552-4469 , p. 72-80 , doi : 10.1038 / nchembio.1141 , PMID 23334546 .
  6. ^ A b Andrew D. Hanson, Christopher S. Henry, Oliver Fiehn, Valérie de Crécy-Lagard: Metabolite Damage and Metabolite Damage Control in Plants . In: Annual Review of Plant Biology . tape 67 , 2016, ISSN  1545-2123 , p. 131-152 , doi : 10.1146 / annurev-arplant-043015-111648 , PMID 26667673 .
  7. ↑ Andreas Bracher, Anurag Sharma, Amanda Starling-Windhof, F. Ulrich Hartl, Manajit Hayer-Hartl: Degradation of potent Rubisco inhibitor by selective sugar phosphatase . In: Nature Plants . tape 1 , 2015, ISSN  2055-0278 , p. 14002 , doi : 10.1038 / nplants.2014.2 , PMID 27246049 .
  8. ↑ Océane Frelin, Lili Huang, Ghulam Hasnain, James G. Jeffryes, Michael J. Ziemak: A directed-overflow and damage-control N-glycosidase in riboflavin biosynthesis . In: The Biochemical Journal . tape 466 , no. 1 , 2015, ISSN  1470-8728 , p. 137–145 , doi : 10.1042 / BJ20141237 , PMID 25431972 , PMC 4477702 (free full text).
  9. ↑ Vincent JJ ​​Martin, Douglas J. Pitera, Sydnor T. Withers, Jack D. Newman, Jay D. Keasling: Engineering a mevalonate pathway in Escherichia coli for production of terpenoids . In: Nature Biotechnology . tape 21 , no. 7 , 2003, ISSN  1087-0156 , p. 796-802 , doi : 10.1038 / nbt833 , PMID 12778056 .
  10. ↑ Sydnor T. Withers, Shayin S. Gottlieb, Bonny Lieu, Jack D. Newman, Jay D. Keasling: Identification of isopentenol biosynthetic genes from Bacillus subtilis by a screening method based on isoprenoid precursor toxicity . In: Applied and Environmental Microbiology . tape 73 , no. 19 , 2007, ISSN  0099-2240 , p. 6277-6283 , doi : 10.1128 / AEM.00861-07 , PMID 17693564 , PMC 2075014 (free full text).