L-phenylalanine biosynthesis i

H:N

L-phenglalanine

phenylalanine
ammonia-lyase (Es): Es-PALI
ammonium
4.3.1. 24/4. 3. 1. 25
glycolysis ll (from fructose 6-phosphate)

Pyruvate

cinnamale
2 H,0
NAD

2H
NADH
acetate

=0

benzoate

cO,

I-phengl-1. 2-propanedione
L-glutamate

2-oxoglutarate

NH
 -phengl-i. 2propanedione

Lglutamale

2-anglutarate

eathinene

NADII S-ealhleoneR
NADIH -reductase (Ls)

I,1.1. .I
NAD"
NAD"

(IR. 87-norephedrine
(S.S-morpdoep
Sodenosy-L"methionine -
S-adenosyl-L-methionime-- (IR 2 s r a a F
8. 28-norpseudoephedrtne
-methyltsnsfarase' (Es): Es-RNHT Es-oNMT
2. 1.L H78 -adenosj-l-hanonstRane
n0s nohocysnine
21.1 Hr

HN
O.

(1S 28)-pseudoephedrine (IR S-ophedrine

S-adenosy-L-mcihionine-. S-adenosy-l-methionine- ( p Es
1S. e (Ls)
ethransfertse Es-PoNMT
{La): s-laNNT
Es-FaNHT
H76
adenospl-thoGsteine adenesg--homocysteine 2.1.L.r6

(HN, 5; (R aS-N-methylephedrine
N-methy lpseudoephedrine
pervlassee: PangnthestsSeeandarjy fetabnite uesgathess- Nitrugen-tamtaiing dndary p egms a ya

Summary
Ephedrine and pseudoephedrine are plant-specific aromatic
amines synthesized by some members of the Ephedra genus
(known as Ma Huang" in Chinese medicine). Ephedrine was first
isolated from Ephedra distachya in 1886 by Nagayoshi Nagai.
The compounds are sympathomimetic in humans - they interact

with the adrenergic receptor system. part of the sympathetie

nervous system. resulting in an inerease in the release of the
neurotransmitters dopamine and serotonin. Ephedrine alkaloids
are used in traditional Chinese medicine for the treatment of
asthma, and are commonly used as stimulants. appetite
suppressants, and decongestants. Ephedrine is listed as an
essential medicine by the World Health Organization for the
prevention of low blood pressure induced by spinal anesthesia.
Early work on the ephedrine biosynthesis pathway. using radio
tracer experiments. showed efficient incorporations of benzoate.
benzaldehyde and cinnamate into the a-carbon atom of the side
chain. and coneluded that a Gg-C unit related to benzaldehyde
or benzoate generates the benzylie fragment of the carbon
skeleton of he Ephedra alkaloids, ruling out the hypothesis that
a Cg-C2 unit is derived directly from the aminophenylpropanoid
system of phenylalanine Lyamasaki73]. A later rodio tracer
study has eoncluded that pyruvate is the precursor of the
aliphatie C2 carbon of the side chain [GrueSorense88.
GrucSorensen89]. Additional work by the authors showed that it
is benzoate rather than benzaldehyde that comtributes the
g-C
unit (GrueSorensen94]. These studies also identified 1-phenyl-
1.2-propanedione and (S)-cathinone as intermediates. even
though these compounds have not been previously detected in or

isolated from any Ephedra species [GrueSorensen94]. The

existence of both compounds was confirmed later in Ephedra
sinica using GC-MS analysis [Krizeuskil0].
Based on the proposed pathway. the first step in the ephedrine
alkaloid biosynthesis is the deamination of L-phenylalanine by
EC 4.3.1. 24. phenylalanine ammonia-lyase. The produet.
cinnamate, is converted into benzoate or benzoyl-CoA by B-
oxidation. a process that results in braneching off from the
common phenglpropanoid pathway. These G6-C units react with
Purvat the dener ef the C2 unit, forming 1-pheny-1. 2-
 unit [GrueSor ensen94J. T hese studies also identific rs

1.2-propanedione and (S)-cathinone as intermediates.

even

detected in
though these compounds have not been previously
or

isolated from any Ephedra species [GrueSorensen94].

The
existence of both compounds was confirmed later in Ephedra
sinica using GC-MS analysis [Krizevskil0].
Based on the proposed pathway. the first step in the ephedrine
alkaloid biosynthesis is the deamination of L-phenylalanine by
EC 4.3.1. 24. phenylalanine ammonia-lyase. The produet.
cinnamate. is converted into benzoate or benzoyl-CoA by B-
oxidation. a process that results in branching off from the
units react with
common phenylpropanoid pathway. These C6-C1
C2 unit. forming 1-phenyl-1. 2-
Pyruvate. the donor of the
propanedione. which is the first intermediate with the basic C6-
C3 skeleton of ephedrine alkaloids.
is
In the latter part of the pathway 1-phenyl-1. 2-propanedione
transaminated to (S)-cathinone, which is reduced in a

stereoselective manner to either (18. 28)- or (1R. 2S)-form

isomers. W-methylation forms ephedrine and pseudoephedrine.
respectively [GrueSorensen94].

At the time the pathway was proposed none of the pathway's

were characterized. and by 2020 only two of them
enzymes
enzyme is EC 4. 3. 1. 24.
have been isolated. The first
and the second is EC
phenylalanine ammonia-lyase [Okada08a].
[Morris18].
2.1. 1. M76. phenylalkylamine N-methyltransferase
sinica. In addition. the activities of
both studied from Ephedra
reductases were demonstrated
two stereo-specific (S)-cathinone
in cell extracts [Krizevskil0].
demonstrated the-
It should be noted that the N-methyltransferase
that
with (S)-cathinone. raising the possibility
highest activity
occur earlier in the pathuway
than previously
N-methylation may
proposed [Morris18).

Credits
Greated 1-Apr-2008 by Zhang P. The Arabidopsis Information
Resource
R, SRI International
Revised 20-May-2020 by Caspi

References
GirueSorensen88: Grue-Sorensen Spenser ID (1988).
G.
American Chemical
of ephedrine. Journal of the
"

"Rigsunthesis