Butyrate kinase

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Butyrate kinase
1X9J.png
Butyrate kinase as an octomer.
Identifiers
EC number 2.7.2.7
CAS number 37278-14-1
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

In enzymology, a butyrate kinase (EC 2.7.2.7) is an enzyme that catalyzes the chemical reaction

ADP + butyryl-phosphate \rightleftharpoons ATP + butyrate

Thus, the two substrates of this enzyme are ADP and butyryl-phosphate, whereas its two products are ATP and butyrate.

This enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing groups (phosphotransferases) with a carboxy group as acceptor. The systematic name of this enzyme class is ATP:butanoate 1-phosphotransferase. This enzyme participates in butyrate metabolism.

This enzyme is transcribed from the gene buk,[1][2] which is part of the ASHKA super family.[3]

Enzyme Mechanism[edit]

Mechanism for butyrate kinase
ADP + butyryl-phosphate \rightleftharpoons ATP + butyrate

The reaction above is a nucleophilic substitution reaction. An electron pair from an oxygen on ADP attacks the phosphorus on butyryl-phosphate, breaking the bond between phosphorus and oxygen to create ATP and butyrate. The arrow-pushing mechanism is shown above.

It should be noted that the reaction can also occur in the reverse direction, as shown below, under certain fermentation conditions.[4][5]

ATP + butyrate \rightleftharpoons ADP + butyryl-phosphate

Structural Studies[edit]

As of 2015, two structures have been solved for this class of enzymes, with PDB accession codes 1SAZ and 1X9J. The study conducted to solve 1SAZ was retracted in 2012 due to fact that the data was used without the permission of the sole custodian.[6]

The investigators of the study that produced the crystallization of 1X9J hypothesized that the enzyme was an octomer formed from dimers.[3] The crystallized form has a radius of 7.5 nm which corresponded to a molecular weight of 380kDa. Because a monomer of buk2 is about 43kDa, it was believed that the enzyme itself was either an octomer or a nonamer. Investigators hypothesized that the enzyme was an octomer since most of the proteins within the ASHKA super family form dimers.

Biological Function[edit]

Butyrate kinase is active within the human colon.[1] To form butyrate, two molecules of acetyl-CoA are combined and reduced to produce butyryl-CoA. Butyryl CoA is then converted into butyrate through two reactions. The first reaction converts butyryl-CoA to butyryl-phosphate by using the phosphotransbutyrylase enzyme.[2] Butyryl-phosphate is then converted into butyrate by using butyrate kinase and in the process, releases ATP.[7][8]

Butyrate plays an important role within cells as it affects cellular proliferation, differentiation, and apoptosis.[9][10]

Because of the significant roles that butyrate plays within cells, it is essential that butyrate kinase is functioning correctly, which can be done through regulation of the enzyme. One study has previously found that butyrate kinase is not regulated by its end-products or other acids such as acetic acid,[11] but more studies need to be conducted to further elucidate the regulation of butyrate kinase.

Disease Relevance[edit]

As stated in the previous section, butyrate is involved with multiple cellular functions. Because of its involvement with these functions, it is hypothesized that butyrate can act as a protective agent against colon cancer and various inflammatory bowel diseases.[7][9][10][12] Butyrate plays a key role in colon cancer by switching its role concerning cellular proliferation and apoptosis depending on the state and conditions of the cell.[9][10] Butyrate also possesses anti-inflammatory effects to decrease colonic inflammation such as ulcerative colitis.[9] One study specifically identified the transcription factor NF-kB as a target of butyrate to decrease the number of pro-inflammatory cytokines.[7]

References[edit]

  1. ^ a b Louis, P; Duncan, SH; McCrae, SI; Millar, J; Jackson, MS; Flint, HJ (April 2004). "Restricted distribution of the butyrate kinase pathway among butyrate-producing bacteria from the human colon.". Journal of Bacteriology 186 (7): 2099–106. PMID 15028695. 
  2. ^ a b Walter, KA; Nair, RV; Cary, JW; Bennet, GN; Papoutsakis, ET (November 1990). "Sequence and arrangement of two genes of the butyrate-synthesis pathway of Clostridium acetobutylicum ATCC 824.". Gene 134 (1): 107–11. PMID 8244020. 
  3. ^ a b Diao, J; Cooper, DR; Sanders, DA; Hasson, MS (June 2003). "Crystallization of butyrate kinase 2 from Thermotoga maritima mediated by vapor diffusion of acetic acid.". Acta Crystallographica. Section D, Biological Crystallography 59 (6): 1100–2. PMID 12777787. 
  4. ^ Wiesenborn, DP; Rudolph, FB; Papoutsakis, ET (February 1989). "Phosphotransbutyrylase from Clostridium acetobutylicum ATCC 824 and its role in acidogenesis". Applied and Environmental Microbiology 55 (2): 317–322. 
  5. ^ Rogers, P (1986). "Genetics and biochemistry of Clostridium relevant to development of fermentation processes". Advanced Application of Microbiology 31: 1–60. 
  6. ^ Diao, Jiasheng; Hasson, Miriam S. (June 2012). "Crystal Structure of Butyrate Kinase 2 from Thermotoga maritima, a Member of the ASKHA Superfamily of Phosphotransferases". Journal of Bacteriology 194 (11): 3033. PMID 22582386. 
  7. ^ a b c Pryde, SE; Duncan, SH; Hold, GL; Stewart, CS; Flint, HJ (December 2002). "The microbiology of butyrate formation in the human colon.". FEMS Microbiolgy Letter 217 (2): 133–9. PMID 12480096. 
  8. ^ Bennett, George; Rudolph, Frederick (1995). "The central metabolic pathway from acetyl-CoA to butyryl-CoA in Clostridium acetobutylicum". FEMS Microbiology Reviews 17 (3): 241–249. doi:10.1016/0168-6445(95)00011-Z. 
  9. ^ a b c d Wächtershäuser, A; Stein, J (August 2000). "Rationale for the luminal provision of butyrate in intestinal diseases". European Journal of Nutrition 39 (4): 164–71. PMID 11079736. 
  10. ^ a b c Sengupta, S; Muir, JG; Gibson, PR (January 2006). "Does butyrate protect from colorectal cancer?". Journal of Gastroenterology and Hepatology 21 (1): 209–18. PMID 16460475. 
  11. ^ Ballongue, Jean; Amine, Jamel; Gay, Peptitdemange; Gay, Robert (July 1986). "Regulation of acetate kinase and butyrate kinase by acids in Clostridium acetobutylicum". FEMS Microbiology Letters 35 (2-3): 295–301. doi:10.1111/j.1574-6968.1986.tb01546.x. 
  12. ^ Seqain, JP; Raingeard de la Blétière, D; Bourreille, A; Leray, V; Gervois, N; Rosales, C; Ferrier, L; Bonnet, C; Blottière, HM; Galmiche, JP (September 2000). "Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease.". Gut 47 (3): 397–403. PMID 10940278. 
  • Hartmanis MG (1987). "Butyrate kinase from Clostridium acetobutylicum". J. Biol. Chem. 262 (2): 617–21. PMID 3027059. 
  • Twarog R and Wolfe RS (1962). "Enzymatic phosphorylation of butyrate". J. Biol. Chem. 237: 2474–2477. PMID 13923331.