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Chemical Mechanism of Myosin‐Catalyzed ATP Hydrolysis

Martin R. Webb, David R. Trentham

10.1002/cphy.cp100108

Source: Supplement 27: Handbook of Physiology, Skeletal Muscle

Originally published: 1983

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Kinetics of ATP Binding and Hydrolysis
2 Nature of ATP Hydrolysis Step
2.1 Oxygen Exchange
2.2 Oxygen Isotope Incorporation
2.3 Positional Isotope Exchange
2.4 Stereochemistry of Phosphoryl Group Transfer
2.5 Structure of Magnesium‐Nucleotide Complexes
3 Perspectives on Mechanism and Function of ATP Hydrolysis in Muscle
Figure 1. Figure 1.

Biochemical events of actomyosin ATPase linked to cross‐bridge cycle. Scheme based on Lymn‐Taylor model 76.
Figure 2. Figure 2.

Simplified mechanism of myosin ATPase. Numbers refer to sequential steps.
Figure 3. Figure 3.

Production of Pi from Mg2+‐ATP catalyzed by myosin subfragment 1 at pH 8.0 and 25°C. A and B result from use of different quenching techniques 110. Initial concentration of subfragment 1 was 4.8 μM and that of [γ‐32P]ATP was 28.4 μM. Measured mean equilibrium constant K2 was 4.26. Arrows, theoretical Pi (13.7%) formed in pre‐steady‐state phase if 1 mol of nucleotide binds per mole of subfragment 1. Subfragment 1 contained either the alkali 1 light chains (filled circles) or alkali 2 light chains (open circles). [From Taylor and Weeds 110.]
Figure 4. Figure 4.

Time course of M* · ATP and M** · ADP · Pi formation in a single turnover of subfragment 1 ATPase. A: 19 μM subfragment 1 mixed with 5 μM [γ‐32P]ATP in a solution of 50 mM KCl, 5 mM MgCl2, and 50 mM Tris [tris(hydroxymethyl)aminomethane] adjusted to pH 8.0 with HCl at 20°C. Inverted filled triangles, fraction of nucleotide present as free ATP; open circles, M* · ATP; upright filled triangles, M** · ADP · Pi. B: computer simulation of fraction of nucleotide present as M* · ATP for various values of Kb in the scheme , where X = ATP, Y = M* · ATP, and Z = M** · ADP · Pi. Values of k+a = 17 s−1 and Kb (= k+b/k−b) = 7 determined from the time course of disappearance of free ATP and the ratio M** · ADP · Pi/M* · ATP at 200 ms. Simulations a, b, c, d, and e: K+b takes values of 50, 100, 150, 200, and 500 s−1, respectively.

Reproduced with permission from Geeves and Trentham 41. Copyright 1982, American Chemical Society
Figure 5. Figure 5.

Time course of ATP synthesis from ADP and Pi in the presence of myosin subfragment 1; 0.4 M [32P]Pi and 50 μM Mg2+‐ADP were incubated with 100 μM subfragment 1 at pH 6.0 and 23°C. [From Mannherz et al. 78.]
Figure 6. Figure 6.

Three possible intermediates in the myosin‐catalyzed ATP hydrolysis step: 1, pentacovalent species; 2, phosphoenzyme; 3, metaphosphate. E, protein residue.
Figure 7. Figure 7.

Mechanism of oxygen exchange between phosphate and water during myosin‐catalyzed ATP hydrolysis. Filled circles, 18O originally present in water becomes incorporated in the intermediates and in phosphate.
Figure 8. Figure 8.

31P NMR spectra of [18O]Pi causes a small upfield shift in the 31P resonance relative to 16O 20,69,71; the shift increases as the number of 18O attached to phosphorus increases. A: 31P NMR spectrum of Pi consisting of 47% [18O4]Pi, 38% [18O3]Pi, 11% [18O2] Pi, 1% [18O1]Pi, and 3% unlabeled Pi. B: spectrum of same Pi (20 mM) after incubation at 22°C for 12 h with myosin subfragment 1 (43.5 μM). Solution also contained 100 mM Tris buffer (pH 8.0), 2.8 mM ADP, 3 mM MgCl2, 0.5 mM EDTA (ethylenediamine tetraacetic acid), and 1.46 μM diadenosine pentaphosphate. The last of these inhibits any adenylate kinase impurity. [From Webb, McDonald, and‐Trentham 122.]
Figure 9. Figure 9.

Mechanism of myosin‐catalyzed medium oxygen exchange between inorganic phosphate and water. Filled circles, 18O.
Figure 10. Figure 10.

18O exchange involving the Pi of M** · ADP · Pi; 43 μM [γ‐18O3]ATP and 86 μM myosin subfragment 1 were mixed in 10 mM Tris (pH 8.0, 20°C), and 2 mM MgCl2. The mixture was acid quenched at various times. Solid circles, %Pi containing 3 18O atoms per molecule; open circles, 2 18O atoms; solid squares, 1 18O atom; solid triangles, no 18O atoms. Curves calculated for k+1 = 2 × 106 M−1 · s−1, k+2 = 80 s−1, and k−2 = 15 s−1 and numbered according to the number of 18O atoms per molecule. Curves are relatively insensitive to minor changes in k+1 and k+2. [From Webb and Trentham 126.]
Figure 11. Figure 11.

31P NMR spectra of the β‐phosphorus of ATPβS. Filled circles, 18O. A: mixture of unlabeled ATPβS (9%), [βγ‐18O]ATPβS (21%), [β‐18O]ATPβS (21%), and [β‐18O; βγ‐18O]ATPβS (49%) arising from labeling of ATPβS with 18O in the β‐ and βγ‐positions, 70% extent. B: ATPβS derived from inorganic [16O, 17O, 18O]thiophosphate product of myosin subfragment 1‐catalyzed hydrolysis of (γ‐R)[βγ‐18O; γ‐18O]ATPγS in 17O‐enriched water.

Adapted from Webb and Trentham 124
Figure 12. Figure 12.

Metal‐nucleotide complexes. A: βγ‐interaction of Mg2+ with ATP. Diastereoisomers (Λ and Δ) arise because of the chirality of phosphorus resulting from coordination of one of the two non‐bridging oxygens to the metal ion. B: Mg2+ and Cd2+ coordinated with ATPβS. Different diastereoisomers form different complexes with Mg2+ and Cd2+ because Mg2+ coordinates to oxygen in preference to sulfur, whereas Cd2+ prefers sulfur. [Data from Jaffe and Cohn 55,57.]
Figure 13. Figure 13.

Electron paramagnetic resonance spectra of ADP‐Mn2+‐subfragment 1 complexes. Spectra, at 35 GHz, taken of a solution containing 1.0 mM myosin subfragment 1, 1.07 mM ADP, 0.50 mM MnCl2, 10 μM diadenosine pentaphosphate in 50 mM Tris buffer (pH 8.0, 3°C). Under these conditions essentially all Mn2+ is in a protein‐bound complex with ADP. A: unlabeled ADP, [α‐17O]‐ADP and [β‐17O]ADP (40% enriched in each position). Peak broadening is observed for [β‐17O]ADP but not for [α‐17O]ADP. B: broken lines, expansion of the first transitions with labeled ADP; solid line, unlabeled ADP. [From Webb et al. 121.]


Figure 1.

Biochemical events of actomyosin ATPase linked to cross‐bridge cycle. Scheme based on Lymn‐Taylor model 76.



Figure 2.

Simplified mechanism of myosin ATPase. Numbers refer to sequential steps.



Figure 3.

Production of Pi from Mg2+‐ATP catalyzed by myosin subfragment 1 at pH 8.0 and 25°C. A and B result from use of different quenching techniques 110. Initial concentration of subfragment 1 was 4.8 μM and that of [γ‐32P]ATP was 28.4 μM. Measured mean equilibrium constant K2 was 4.26. Arrows, theoretical Pi (13.7%) formed in pre‐steady‐state phase if 1 mol of nucleotide binds per mole of subfragment 1. Subfragment 1 contained either the alkali 1 light chains (filled circles) or alkali 2 light chains (open circles). [From Taylor and Weeds 110.]



Figure 4.

Time course of M* · ATP and M** · ADP · Pi formation in a single turnover of subfragment 1 ATPase. A: 19 μM subfragment 1 mixed with 5 μM [γ‐32P]ATP in a solution of 50 mM KCl, 5 mM MgCl2, and 50 mM Tris [tris(hydroxymethyl)aminomethane] adjusted to pH 8.0 with HCl at 20°C. Inverted filled triangles, fraction of nucleotide present as free ATP; open circles, M* · ATP; upright filled triangles, M** · ADP · Pi. B: computer simulation of fraction of nucleotide present as M* · ATP for various values of Kb in the scheme , where X = ATP, Y = M* · ATP, and Z = M** · ADP · Pi. Values of k+a = 17 s−1 and Kb (= k+b/k−b) = 7 determined from the time course of disappearance of free ATP and the ratio M** · ADP · Pi/M* · ATP at 200 ms. Simulations a, b, c, d, and e: K+b takes values of 50, 100, 150, 200, and 500 s−1, respectively.

Reproduced with permission from Geeves and Trentham 41. Copyright 1982, American Chemical Society


Figure 5.

Time course of ATP synthesis from ADP and Pi in the presence of myosin subfragment 1; 0.4 M [32P]Pi and 50 μM Mg2+‐ADP were incubated with 100 μM subfragment 1 at pH 6.0 and 23°C. [From Mannherz et al. 78.]



Figure 6.

Three possible intermediates in the myosin‐catalyzed ATP hydrolysis step: 1, pentacovalent species; 2, phosphoenzyme; 3, metaphosphate. E, protein residue.



Figure 7.

Mechanism of oxygen exchange between phosphate and water during myosin‐catalyzed ATP hydrolysis. Filled circles, 18O originally present in water becomes incorporated in the intermediates and in phosphate.



Figure 8.

31P NMR spectra of [18O]Pi causes a small upfield shift in the 31P resonance relative to 16O 20,69,71; the shift increases as the number of 18O attached to phosphorus increases. A: 31P NMR spectrum of Pi consisting of 47% [18O4]Pi, 38% [18O3]Pi, 11% [18O2] Pi, 1% [18O1]Pi, and 3% unlabeled Pi. B: spectrum of same Pi (20 mM) after incubation at 22°C for 12 h with myosin subfragment 1 (43.5 μM). Solution also contained 100 mM Tris buffer (pH 8.0), 2.8 mM ADP, 3 mM MgCl2, 0.5 mM EDTA (ethylenediamine tetraacetic acid), and 1.46 μM diadenosine pentaphosphate. The last of these inhibits any adenylate kinase impurity. [From Webb, McDonald, and‐Trentham 122.]



Figure 9.

Mechanism of myosin‐catalyzed medium oxygen exchange between inorganic phosphate and water. Filled circles, 18O.



Figure 10.

18O exchange involving the Pi of M** · ADP · Pi; 43 μM [γ‐18O3]ATP and 86 μM myosin subfragment 1 were mixed in 10 mM Tris (pH 8.0, 20°C), and 2 mM MgCl2. The mixture was acid quenched at various times. Solid circles, %Pi containing 3 18O atoms per molecule; open circles, 2 18O atoms; solid squares, 1 18O atom; solid triangles, no 18O atoms. Curves calculated for k+1 = 2 × 106 M−1 · s−1, k+2 = 80 s−1, and k−2 = 15 s−1 and numbered according to the number of 18O atoms per molecule. Curves are relatively insensitive to minor changes in k+1 and k+2. [From Webb and Trentham 126.]



Figure 11.

31P NMR spectra of the β‐phosphorus of ATPβS. Filled circles, 18O. A: mixture of unlabeled ATPβS (9%), [βγ‐18O]ATPβS (21%), [β‐18O]ATPβS (21%), and [β‐18O; βγ‐18O]ATPβS (49%) arising from labeling of ATPβS with 18O in the β‐ and βγ‐positions, 70% extent. B: ATPβS derived from inorganic [16O, 17O, 18O]thiophosphate product of myosin subfragment 1‐catalyzed hydrolysis of (γ‐R)[βγ‐18O; γ‐18O]ATPγS in 17O‐enriched water.

Adapted from Webb and Trentham 124


Figure 12.

Metal‐nucleotide complexes. A: βγ‐interaction of Mg2+ with ATP. Diastereoisomers (Λ and Δ) arise because of the chirality of phosphorus resulting from coordination of one of the two non‐bridging oxygens to the metal ion. B: Mg2+ and Cd2+ coordinated with ATPβS. Different diastereoisomers form different complexes with Mg2+ and Cd2+ because Mg2+ coordinates to oxygen in preference to sulfur, whereas Cd2+ prefers sulfur. [Data from Jaffe and Cohn 55,57.]



Figure 13.

Electron paramagnetic resonance spectra of ADP‐Mn2+‐subfragment 1 complexes. Spectra, at 35 GHz, taken of a solution containing 1.0 mM myosin subfragment 1, 1.07 mM ADP, 0.50 mM MnCl2, 10 μM diadenosine pentaphosphate in 50 mM Tris buffer (pH 8.0, 3°C). Under these conditions essentially all Mn2+ is in a protein‐bound complex with ADP. A: unlabeled ADP, [α‐17O]‐ADP and [β‐17O]ADP (40% enriched in each position). Peak broadening is observed for [β‐17O]ADP but not for [α‐17O]ADP. B: broken lines, expansion of the first transitions with labeled ADP; solid line, unlabeled ADP. [From Webb et al. 121.]

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Article Title: Chemical Mechanism of Myosin‐Catalyzed ATP Hydrolysis
 

How to Cite

Martin R. Webb, David R. Trentham. Chemical Mechanism of Myosin‐Catalyzed ATP Hydrolysis. Compr Physiol 2011, Supplement 27: Handbook of Physiology, Skeletal Muscle: 237-255. First published in print 1983. doi: 10.1002/cphy.cp100108