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L-lysine = (3S)-3,6-diaminohexanoate
L-lysine = (3S)-3,6-diaminohexanoate
L-lysine = (3S)-3,6-diaminohexanoate
lysine 2,3-aminomutase (LAM) is a radical S-adenosyl-L-methionine (SAM) enzyme, catalysis is initiated by reductive cleavage of the S-adenosyl-L-methionine S-C5' bond, which creates the highly reactive 5'-deoxyadenosyl radical, the same radical generated by homolytic Co-C bond cleavage in B12 radical enzymes. The S-adenosyl-L-methionine surrogate S-3',4'-anhydroadenosyl-L-methionine can replace S-adenosyl-L-methionine as a cofactor in the isomerization of L-alpha-lysine to L-beta-lysine by 2,3-LAM, via the stable allylic anhydroadenosyl radical. The holoenzyme coordinates a pyridoxal 5'-phosphate cofactor through formation of an internal aldimine with Lys337. As L-alpha-lysine binds, pyridoxal 5'-phosphate forms an external aldimine linkage to the alpha-amine group of the substrate. Reductive cleavage of S-adenosyl-L-methionine leads to formation of 5'-dA radical. Electron transfer from the [4Fe4S]1+ cluster initiates radical S-adenosyl-L-methionine reactions by reductive cleavage of the S-C5' bond to create the highly reactive 5'-deoxyadenosyl radical
L-lysine = (3S)-3,6-diaminohexanoate
lysine 2,3-aminomutase catalyzes S-adenosylmethionine and pyridoxal 5'-phosphate-dependent interconversion of L-lysine and L-beta-lysine, the reaction follows the pattern of adenosylcobalamin-dependent rearrangements, with hydrogen transfer from lysine through the adenosyl-C5' of S-adenosyl-L-methionine to beta-lysine. S-Adenosyl-L-methionine is cleaved to form 5'-deoxyadenosine-5'-yl followed by abstraction of C3(H) from pyridoxal-5'-phosphate-alpha-lysine aldimine to form PLP-R-lysine-3-yl. Pyridoxal 5'-phosphate-alpha-lysine-3-yl isomerizes to pyridoxal-beta-lysine-2-yl, and a hydrogen abstraction from 5'-deoxyadenosine regenerates 5'-deoxyadenosine-5'-yl and releases beta-lysine, 4 radicals in the reaction. Identification of radical intermediates. Reaction mechanism, detailed overview
L-lysine = (3S)-3,6-diaminohexanoate
mechanism
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L-lysine = (3S)-3,6-diaminohexanoate
reaction proceeds by a substrate radical rearrangement mechanism, in which the external aldimine formed between pyridoxal phosphate and Lys is initially converted into a lysyl-radical intermediate by hydrogen abstraction from C3
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L-lysine = (3S)-3,6-diaminohexanoate
only the migrating (3-pro-R) hydrogen of alpha-Lys is involved in the intermolecular exchange
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L-lysine = (3S)-3,6-diaminohexanoate
substantially or completely intermolecular hydrogen transfer
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L-lysine = (3S)-3,6-diaminohexanoate
the active site facilitates hydrogen atom transfer by enforcing van der Waals contact between radicals and their reacting partners thus minimizing side reactions of the highly active species
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L-lysine
(3S)-3,6-diaminohexanoate
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L-lysine
(3S)-3,6-diaminohexanoic acid
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r
L-lysine
L-beta-lysine
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-
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r
S-adenosylmethionine
5'-deoxyadenosylmethionine
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-
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r
(S)-lysine
(S)-beta-lysine
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-
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r
L-2-aminobutyrate
L-3-aminobutyrate
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very low activity
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?
L-alanine
beta-alanine
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very low activity
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-
?
L-Lys
(3S)-3,6-diaminohexanoic acid
L-lysine
(3S)-3,6-diaminohexanoate
L-lysine
(3S)-3,6-diaminohexanoic acid
additional information
?
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L-Lys
(3S)-3,6-diaminohexanoic acid
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?
L-Lys
(3S)-3,6-diaminohexanoic acid
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?
L-Lys
(3S)-3,6-diaminohexanoic acid
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-
-
?
L-Lys
(3S)-3,6-diaminohexanoic acid
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-
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?
L-Lys
(3S)-3,6-diaminohexanoic acid
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?
L-Lys
(3S)-3,6-diaminohexanoic acid
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-
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?
L-Lys
(3S)-3,6-diaminohexanoic acid
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(2S)-alpha-Lys
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?
L-Lys
(3S)-3,6-diaminohexanoic acid
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the radical intermediate has (S)-configuration, and stereochemistry is determined by the conformation of the lysine side chain in the active site
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L-lysine
(3S)-3,6-diaminohexanoate
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L-lysine
(3S)-3,6-diaminohexanoate
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initial step in the catabolismus of L-lysine to acetyl-CoA and ammonia
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?
L-lysine
(3S)-3,6-diaminohexanoate
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initial step in the catabolismus of L-lysine to acetyl-CoA and ammonia
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?
L-lysine
(3S)-3,6-diaminohexanoate
-
initial step in the catabolismus of L-lysine to acetyl-CoA and ammonia
-
?
L-lysine
(3S)-3,6-diaminohexanoic acid
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-
-
-
?
L-lysine
(3S)-3,6-diaminohexanoic acid
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highly specific for L-lysine
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r
additional information
?
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lysine 2,3-aminomutase (LAM) catalyzes S-adenosylmethionine and pyridoxal-5'-phosphate dependent interconversion of L-lysine and L-beta-lysine. Reaction of trans-4,5-dehydro-L-lysine with the enzyme and S-adenosyl-L-methionine leads to the 4,5-dehydro-radical. Reductive cleavage of S-adenosyl-L-methionine to the 5'-deoxyadenosyl radical by enzyme LAM, mechanism, overview
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additional information
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substrate 13C ENDOR measurements
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additional information
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the equilibrium constants for reaction favor the beta-isomers. The value of the equilibrium constant is independent of pH between pH 6 and pH 11. It is temperature-dependent and ranges from 10.9 at 4°C to 6.8 at 65°C. Reaction is enthalpy-driven
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?
additional information
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the enzyme does not display detectable activity toward D-lysine, L-glutamate, L-glutamine, L-threonine, L-homoserine, L-tyrosine, L-phenylalanine, L-valine, L-leucine, L-isoleucine, L-histidine, L-tryptophan, L-ornithine, or L-arginine
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D165N
about 0.1% of wild-type activity, 0.23 mol iron and 0.13 mol sulfur per mol of subunit
D172N
no catalytic activity, 0.43 mol iron and 0.13 mol sulfur per mol of subunit
D293N
no catalytic activity, 0.97 mol iron and 0.05 mol sulfur per mol of subunit. Involved in binding of epsilon-aminium and alpha-carboxylate groups of substrate
D330A
no catalytic activity, 1.9 mol iron and 1.3 mol sulfur per mol of subunit. Involved in binding of epsilon-aminium and alpha-carboxylate groups of substrate
D330N
no catalytic activity, 1.0 mol iron and 0.63 mol sulfur per mol of subunit
D96N
less than 1% of wild-type activity, 1.2 mol iron and 0.95 mol sulfur per mol of subunit
E236Q
about 1% of wild-type activity, 0.7 mol iron and 0.5 mol sulfur per mol of subunit
E86Q
about 20% of wild-type activity, 0.5 mol iron and 0.4 mol sulfur per mol of subunit
R130K
no catalytic activity, 0.2 mol iron and 0.3 mol sulfur per mol of subunit
R130Q
no catalytic activity, 0.42 mol iron and 0.2 mol sulfur per mol of subunit
R134K
no catalytic activity, 1.5 mol iron and 1.5 mol sulfur per mol of subunit
R134Q
no catalytic activity, 2.8 mol iron and 2.7 mol sulfur per mol of subunit. Involved in binding of epsilon-aminium and alpha-carboxylate groups of substrate
R135K
about 16% of wild-type activity, 2.4 mol iron and 1.6 mol sulfur per mol of subunit
R135Q
about 1.5% of wild-type activity, 1.8 mol iron and 1.5 mol sulfur per mol of subunit
R136Q
about 1.2% of wild-type activity, 0.48 mol iron and 0.35 mol sulfur per mol of subunit
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Aberhart, D.J.; Gould, S.J.; Lin, H.J.; Thiruvengadam, T.K.; Weiller, B.H.
Stereochemistry of lysine 2,3-aminomutase isolated from Clostridium subterminale strain SB4
J. Am. Chem. Soc.
105
5461-5470
1983
Clostridium subterminale, Clostridium subterminale SB4
-
brenda
Song, K.B.; Frey, P.A.
Molecular properties of lysine-2,3-aminomutase
J. Biol. Chem.
266
7651-7655
1991
Clostridium subterminale, Clostridium subterminale SB4
brenda
Aberhart, D.J.
Studies of the mechanism of lysine 2,3-aminomutase
J. Chem. Soc. Perkin Trans. I
1988
343-350
1988
Clostridium subterminale, Clostridium subterminale SB4
-
brenda
Aberhart, D.J.; Cotting, J.A.
Mechanistic studies on lysine 2,3-aminomutase: carbon-13-deuterium crossover experiments
J. Chem. Soc. Perkin Trans. I
1988
2119-2122
1988
Clostridium subterminale
-
brenda
Lieder, K.W.; Booker, S.; Ruzicka, F.J.; Beinert, H.; Reed, G.H.; Frey, P.A.
S-Adenosylmethionine-dependent reduction of lysine 2,3-aminomutase and observation of the catalytically functional iron-sulfur centers by electron paramagnetic resonance
Biochemistry
37
2578-2585
1998
Clostridium subterminale
brenda
Frey, P.A.
Lysine 2,3-aminomutase: is adenosylmethionine a poor man's adenosylcobalamin?
FASEB J.
7
662-670
1993
Clostridium subterminale
brenda
Cosper, N.J.; Booker, S.J.; Ruzicka, F.; Frey, P.A.; Scott, R.A.
Direct FeS cluster involvement in generation of a radical in lysine 2,3-aminomutase
Biochemistry
39
15668-15673
2000
Clostridium subterminale
brenda
Wu, W.; Booker, S.; Lieder, K.W.; Bandarian, V.; Reed, G.H.; Frey, P.A.
Lysine 2,3-aminomutase and trans-4,5-dehydrolysine: characterization of an allylic analogue of a substrate-based radical in the catalytic mechanism
Biochemistry
39
9561-9570
2000
Clostridium subterminale
brenda
Chen, D.; Walsby, C.; Hoffman, B.M.; Frey, P.A.
Coordination and mechanism of reversible cleavage of S-adenosylmethionine by the [4Fe-4S] center in lysine 2,3-aminomutase
J. Am. Chem. Soc.
125
11788-11789
2003
Clostridium subterminale
brenda
Lepore, B.W.; Ruzicka, F.J.; Frey, P.A.; Ringe, D.
The X-ray crystal structure of lysine-2,3-aminomutase from Clostridium subterminale
Proc. Natl. Acad. Sci. USA
102
13819-13824
2005
Clostridium subterminale (Q9XBQ8), Clostridium subterminale
brenda
Behshad, E.; Ruzicka, F.J.; Mansoorabadi, S.O.; Chen, D.; Reed, G.H.; Frey, P.A.
Enantiomeric free radicals and enzymatic control of stereochemistry in a radical mechanism: the case of lysine 2,3-aminomutases
Biochemistry
45
12639-12646
2006
Clostridium subterminale, Escherichia coli
brenda
Chen, D.; Frey, P.A.; Lepore, B.W.; Ringe, D.; Ruzicka, F.J.
Identification of structural and catalytic classes of highly conserved amino acid residues in lysine 2,3-aminomutase
Biochemistry
45
12647-12653
2006
Clostridium subterminale (Q9XBQ8), Clostridium subterminale SB4 (Q9XBQ8), Clostridium subterminale SB4
brenda
Hinckley, G.T.; Frey, P.A.
Cofactor dependence of reduction potentials for [4Fe-4S]2+/1+ in lysine 2,3-aminomutase
Biochemistry
45
3219-3225
2006
Clostridium subterminale, Clostridium subterminale SB4
brenda
Wang, S.C.; Frey, P.A.
Binding energy in the one-electron reductive cleavage of S-adenosylmethionine in lysine 2,3-aminomutase, a radical SAM enzyme
Biochemistry
46
12889-12895
2007
Clostridium subterminale, Clostridium subterminale SB4
brenda
Chen, D.; Tanem, J.; Frey, P.A.
Basis for the equilibrium constant in the interconversion of L-lysine and L-beta-lysine by lysine 2,3-aminomutase
Biochim. Biophys. Acta
1774
297-302
2007
Clostridium subterminale, Clostridium subterminale SB4
brenda
Lees, N.S.; Chen, D.; Walsby, C.J.; Behshad, E.; Frey, P.A.; Hoffman, B.M.
How an enzyme tames reactive intermediates: positioning of the active-site components of lysine 2,3-aminomutase during enzymatic turnover as determined by ENDOR spectroscopy
J. Am. Chem. Soc.
128
10145-10154
2006
Clostridium subterminale, Clostridium subterminale SB4
brenda
Frey, P.A.; Hegeman, A.D.; Ruzicka, F.J.
The radical SAM superfamily
Crit. Rev. Biochem. Mol. Biol.
43
63-88
2008
Clostridium subterminale (Q9XBQ8)
brenda
Frey, P.A.; Reed, G.H.
Pyridoxal-5'-phosphate as the catalyst for radical isomerization in reactions of PLP-dependent aminomutases
Biochim. Biophys. Acta
1814
1548-1557
2011
Clostridium subterminale, Clostridium subterminale SB4
brenda
Ruzicka, F.J.; Frey, P.A.
Kinetic and spectroscopic evidence of negative cooperativity in the action of lysine 2,3-aminomutase
J. Phys. Chem. B
114
16118-16124
2010
Clostridium subterminale, Clostridium subterminale SB4
brenda
Frey, P.
Travels with carbon-centered radicals. 5'-Deoxyadenosine and 5'-deoxyadenosine-5'-yl in radical enzymology
Acc. Chem. Res.
47
540-549
2014
Clostridium subterminale (Q9XBQ8), Clostridium subterminale SB4 (Q9XBQ8)
brenda
Horitani, M.; Byer, A.S.; Shisler, K.A.; Chandra, T.; Broderick, J.B.; Hoffman, B.M.
Why nature uses radical SAM enzymes so widely electron nuclear double resonance studies of lysine 2,3-aminomutase show the 5-dAdo? Free radical is never free
J. Am. Chem. Soc.
137
7111-7121
2015
Clostridium subterminale (Q9XBQ8), Clostridium subterminale SB4 (Q9XBQ8), Clostridium subterminale SB4
brenda