Molecular conformation of L-DOPA

Vol. 41, No. 2, 1970

BIOCHEMICAL

AND BIOPHYSICAL RESEARCH COMMUNICATIONS

MOLECULAR CONFORMATION OF L-DOPA J.W.

Becker,

Y.T.

Thathachari

and P.G.

Simpson

Departments of Chemistry and Dermatology, Stanford University, Stanford, Calif 94305 ReceivedSeptember 15, 1970 SUMMARY: The structure has been determined Its

function. reported Its

for

crystal

conformation

any aromatic

aminoacid,

of hydrogen

and all

the

recognizes

There

and related

structure

step

interest

as it

disease.

X-ray

of L-DOPA with

(1).

a Hilger

reaction

is

the molecules

therefore

in the

component

units

of the

(L-DOPA)

of melanins

of melanin

nitrogen

whereby

determination

of L-tyrosine

as

and their

to L-DOPA is

from L-tyrosine,

the

its

The compound is one of additional shown to reduce

Here the

conversion

seems to be involved diffraction

their

and role

oxidation

the

reactions

3,4 dihydroxyphenylalanine structure

so far

participate.

interest

the

that

dimensional

and shape of

of biopolymers,

Patterson

compound.

the particular

structure

has been recently

decarboxylation

METHODS:

the

precursor

of Parkinson's by

of

of

or related

the oxygens,

causing

in the biosynthesis

physiological

all

We undertook

The enzymic

precursors.

another

from

by a three

has been considerable

conformation

of a study

peptide

of melanins

of the

different

of biochemical

to the

structures.

molecular

is

the NH3 and OH groups

The specificity

of the

first

of

precursor

analysis

characterized

bonds in which

to be related

involved.

part

is

hydrogens

INTRODUCTION:

study

by a new systematic

structure

one molecule

a biological

molecular

network

believed

of L-DOPA,

data & Watts

symptoms

of L-DOPA to dopamine

12).

were collected Y 290 computer 444

the

for

a single

controlled

four

crystal circle

Vol. 41, No. 2,197O

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

diffractometer

using

Cu Ko(&radiation

Li F monochromator. than

668 unique

57O were used after

effects.

factors

procedure

crystal

analysis

information of the best

(4).

Harker

fit

with

were located refined

by the

a doubly

bent

Bragg angles

less

and polarization scale

and

by the method of Wilson

(3).

image'

method,

a new

based on Patterson

a minimum of noncrystallographic

trial

trial

Patterson

from difference

Fourier

squares

atoms chosen from

images were derived

the observed

by least

Lorentz

determination

From a set of region,

with

'reliable

structure

using

from

was made and the

were obtained

was solved

function

for

correction

The structure for

reflections

correcting

No absorption

temperature

reflected

that

function. maps.

technique.

The

the analysis

provided

The hydrogen The structure

-'reliability

the positions

was factor'

was .09.

RESULTS Unit

Cell:

The unit

b = 13.607

Monoclinic

Molecular

with

the value

Conformation:

of L-DOPA is quite

phenyl

group

(7).

same conformation

correspond

.003 A and y

per unit

is

from that While

~l=300°

, 180'

position

with

the plane

the

g. cm -3

by flotation. 1 that

the

conformation

(5),

dopamine

nitrogen

is close reverse

carboxyl

These three positions

the

single

N CdCfihasXl=

445

with

true

(8) have

conformations angles

bond Ca(C@. O".

is

(6)

to the

and nitrogen

Dopamine and noradrenaline

staggered

and 60° around

Clyin

was 1.512

away the

both

+ -02 O.

based on these

of L-tyrosine

is farther

as L-tyrosine.

to the three

= 97.55

cell

in L-DOPA the

group.

+ - .003 A;

density

seen from Fig.

In L-phenylalanine

to the phenyl

a = 6.044

1.51 + _ .02 obtained

and the carboxyl

L-tyrosine.

are close

It

are:

The calculated

different

or L-phenylalanine

the

P 21.

t

and assuming two molecules

in agreement

for

parameters

+ .003 A; c = 5.311

Spacegroup: data

cell

of rotation The eclipsed

The numbering

of

Vol. 41, No. 2, 1970

BIOCHEMICAL

AND BIOPHYSICAL RESEARCH COMMUNICATIONS

(3)

Fig.

1. Molecular

3. L-tyrosine;

the

place

suggested

the bulky

are expected

group

to be sterically

by rotations

angles

being

about

denoted

corresponding

present).

They relate the

of

seem to follow of

the

1.

al

(9).

between

group

is

Values

in

from choice

the planar of

aminoacids

The bond lengths

to CC( )and also

the corresponding

arezy/'s,

?,iJi, y&

in the

carboxyl

nearly (when

of the N C@bond from the deviation

180° apart phenyl

is about and relate

group.

and related

and angles 446

to 300°

The conformations

The conformation

x1.

the

ofXlclose

and CfiCv

There

In L-DOPA this

follow

N and H (bonded

deviation

also

angles

(10).

and x%.

to the

a number of aromatic

in Table

et

rotation

to the two oxygens

carboxyl.

the Cfi

the

favored

The two 3% Is, %,2jandX22are deviation

2. dopamine;

The phenyl

the bonds Co(C'

by w

180° apart

of

of

by Edsall

aromatic

differ

plane

1. L-DOPA;

the paper.

atoms and the designation

conventions

of

and 4. L-phenylalanine. of

the plane

Conformations

y

14O. to the

and %z parameters

structures

of L-DOPA are not

are given different

Vol. 41, No. 2, 1970

Table

BIOCHEMICAL

AND BIOPHYSICAL RESEARCH COMMUNICATIONS

1

Conformation

parameters

and related C6(-C/j

compounds.

and/Xlabout

for

L-DOPA and other

The angles y

Cp

aromatic

are about

aminoacids

Co(-

C',

Xlabout

- C v.

VL

y2'

Xl

L-DOPA

166

344

294

113

291

L-DOPA H Cl(11)

168

346

298

111

289

N acetyltyrosinamide(l2)

---

335

306

109

293

L-tyrosine

H Cl(S)

150

324

185

64

244

H Br(5)

155

322

187

65

250

149

327

190

65

242

174

77

259

s-e

176

82

263

Aminoacid

or related

II Glycyl

L-tyrosine

compound

H Cl(l3)

Dopamine H Cl(6)

---

Noradrenaline

---

H Cl(8)

x22

Xaz

Glycylphenylalanylglycine(l4)

---

314

185

102

278

L-threonyl L-phenylalanine p nitrobenzyl ester H Br (15)

117

299

176

87

268

Gephenylalanine

178

358

62

84

262

from those

H Cl(7)

of other

HYDROGENBONDS: by a three

compounds.

The crystal

dimensional

the nitrogen

and all

network

in the hydrogen

adjacent

molecule

and 02 of

adjacent

molecule

and

disorder

The nitrogen

two adjacent to 0

bonds.

7

characterized All

the oxygens,

in the NH8 and OH groups

bonding.

O7

of L-DOPA is

of hydrogen

the hydrogens

involved

a twofold

structure

is

molecules;

of two adjacent

in the hydrogen 447

bound to 0

7.

are

bonded to 01 of an 05

to 01 of an

molecules.

There

is

Vol. 41, No. 2,197O

DISCUSSION:

In its

structure: It

BIOCHEMICAL

unlikely

its

preferred

the

related

(CHR) -

that

requirements was being

might

(11).

heavy

derivative

is

linked

hydrogen are

the

It

of

the

same.

conformations

is

computed

readily

as well

to the

the dispositions in the

and if

they

have

these

compounds.

found

the

the

other

that

size

This

which

significance

from

the

conformational

of these

structure tyrosyl

in the

cell. This

unchanged. we report of

the

is

closely or noradrenaline.

conformational

group

reactions

changes involving we

in N acetyltyrosinamide and close

change may be related

448

unit

cell

of L-DOPA was determined

of L-tyrosine

groups.

molecules.

the unit

L-phenylalanine

to the biochemical

of the that

remains

from that

dopamine,

any relation After

differ

crystal

and shape of

the L-DOPA conformation

L-tyrosine,

conformation

(12) was different L-DOPA.

the molecule

know the

H Cl

of adjacent

however

We do not yet

conformation

zwitterion

of

compound:

data

the different

However

The conformation

related

report

bond to N and 02. as compared

conformation

bond

H Cl derivatives

of the molecules

natural

the as its

and orientation

its

as this

from these

seen that

zwitterion

changes

indicate

In all

the hydrogen Just

and the position

would probably

and

bonds to the

ask if

changes.

of

of L-DOPA H Cl was made available

by altering

in slight

by us is

In L-DOPA H Cl as in other

bond requirements

They result

solutions.

noradrenaline

One might

parameters

1.

by hydrogen

accommodated

reported

by hydrogen

conformational

the result

of L-DOPA in crystals

the

linked

the oxygens.

in Table

in neutral

of L-DOPA found

dopamine,

atom is

The conformation

are included

Cl is

conformation

also

zwitterion

to the H Cl or H Br derivatives.

force

prepared

found

However

correspond

and some of

to us

the

(coo)-

compounds L-tyrosine,

compounds the

nitrogen

form L-DOPA has the

conformation.

L-phenylalanine these

crystalline

(NH~)+ -

is not

AND BIOPMYSICAL RESEARCH COMMUNICATIONS

to that

of

to the presence

Of

Vol. 4 1, No. 2, 1970

BIOCHEMICAL

ACKNOWLEDGEMENTS: Partial FR-00311,

IEAA 405,

the Center Research N.I.H.

for

predoctoral

for

the

collection

for

kindly

sending

research

the Advanced

Materials

Fund(Grant

AND BIOPHYSICAL RESEARCH COMMUNICATIONS

fellowship of

Research

Research

3068-A5),

supports

Project

at Stanford

Du Pont young (J.W.B).

the diffraction

us the data

from N.I.H.

for

University, faculty

We thank data

Agency

grant Dr.

and Dr.

T.E.

CA-10846, through Petroleum and Hopkins

R. Jandacek

L DOPA H Cl.

REFERENCES: 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

W.C. Evans and H.S. Raper, Biochem. J. 2, 2162 (1937) E.M. Sedgwick, New Sci., 44, 234 (1969) A.J.C. Wilson, Nature, 150,151 (1942) C. Djerassi, S.H. Brownand P.G. Simpson, J. Am. Chem. Sot. 90,2445 (1968) S.H. Brown and P.G. Simpson, Acta Cryst., in press J.H. Karl, J.W. Becker, E.R. Sholkovitz, T.E. Hopkins and P.G. Simpson - in preparation R. Srinivasan, Proc. Ind. Acad. Sci. g, ii0 (1959) 11 II (1959) R. Bergin and D. Carlstrpm, Acta Crysc:B 24, 1506 (1968) B.K. Vainshtein and G.V. Gurskaya, Dokl. Akad. Nauk. SSSR, 156,312 (1964) D. Carlstrom and R. Bergin, Acta Cryst., 23,313 (1967) J.T. Edsall, P.J. Flory, J.C. Kendrew, A.M. Liquor?, G. Nemethy, G.N. Ramachandran and H.A. Scheraga, J. Biol. Chem., 241, 1004 (1966) A.V. Lakshminarayanan, V. Sasisekharan and G.N. Ramachandran, in 'Conformations of Biopolymers', G.N. Ramachandran Ed. (Academic Press, New York, 1967), p. 61. R.J. Jandacek and K. Earle - private communication J.H. Kahrl and P.G. Simpson - in preparation D.W. Smits and E.H. Wiebenga, Acta Cryst., 6, 531 (1953) R,E. Mal;sh and J.P. Glusker, Acta Cryst., 16, 1110 (1961) M. Mallikarjunan, S. Thyagaraja Rao, K. Venkatesan and V. Raghupati Sarma, Acta Cryst., B 25, 220 (1969)

449