Biocatalysis The Outcast

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DOI: 10.1002/cctc.200900126
Biocatalysis: The Outcast
Ruslan Yuryev and Andreas Liese*[a]
The phenomena of life and catalysis are
inevitably interrelated. Billions of years
ago catalysis played an integral role in
the origin of life, and for centuries we
have exploited catalysis to make our
lives easier. However, the ways that
catalysis is implemented within living
systems and by thinking beings, such as
humans, are quite different at first
glance. This difference was initially realiz-
ed in the early days of catalysis as a sci-
entific discipline and was thus expressed
in the classification of catalysis, which is
still generally adopted and even referred
to on the front cover of this journal. It is
widely assumed that there are three
distinct branches of catalysis: hetero-
geneous, homogeneous and biocatalysis
(Figure 1). However, such a division is
obviously literally inadequate. According
to the definitions taken from the
renowned Encyclopaedia Britannica,[1] “In
homogeneous catalysis, the catalyst is
molecularly dispersed in the same phase
(usually gaseous or liquid) as the reac-
tants. In heterogeneous catalysis the re-
actants and the catalyst are in different
phases, separated by a phase boundary”,
catalysis can be either homogeneous
(same phase) or heterogeneous (differ-
ent phases). No third category is
allowed, as in the “male–female” differ-
entiation. The situation becomes even
more confusing if one considers that
biocatalysis is either homogeneous or
heterogeneous, just like conventional
chemical catalysis (Figure 2). So, why is
biocatalysis treated as a separate class?
What is so special about it?
Analysis of this question from a histor-
ical perspective may help in finding a
correct answer. The classification of catal-
ysis as heterogeneous or homogeneous
was mentioned as far back as 1919, in
the fundamental book Catalysis in Theory
and Practice by Rideal and Taylor,[2] in the
exact period when catalytic technology
started to expand exponentially in indus-
try. At that time, such a division, based
on the macroscopic behavior of catalytic
systems, was of special interest for prac-
tical applications, whereas the physical
state of the catalyst and reactants (solid,
liquid or gaseous) predetermined design
of the reactor used for the catalytic pro-
cesses. A separate chapter in this book,
entitled “Ferments and Enzymes,” was
devoted to biocatalysis. Although the
precise nature of enzymes was not clear
at this point, these substances were
known to satisfy three criteria required
for being a catalyst : a) the chemical
composition of the catalytic agents is
unchanged on completion of the reac-
tion process; b) minimal amounts of the
catalytic agent are adequate for the
transformation of large quantities of the
reacting substances; c) the catalyst
cannot affect the final state of equilibri-
um. Consequently it was concluded that:
“enzymes must therefore be regarded as
catalytic agents, but we shall have occa-
sion to note in the following pages
many interesting peculiarities in the
nature and mode of action of enzyme
catalysts, which slightly differentiate
enzyme action from ordinary catalytic
processes.”[2] These “interesting peculiari-
ties” were the colloidal nature of en-
zymes, extreme specificity as their “most
mysterious property”[2] (one reaction—
Figure 1. Conventional application-driven and alternative origin-based classifications of catalysis.
Figure 2. Biocatalysis, like chemocatalysis, can be either homogeneous or heterogeneous.
[a] R. Yuryev, Prof. Dr. A. Liese
Institute of Technical Biocatalysis
Hamburg University of Technology
Denickestrasse 15, 21073 Hamburg (Germany)
Fax: (+ 49) 40-42878-2127
E-mail : liese@tuhh.de
ChemCatChem 2010, 2, 103 – 107 � 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 103
VIEWPOINTS
one enzyme), stereo- and regioselectivity,
and relative instability and narrow opera-
tional space with respect to temperature
and pH. Notably, in the second edition
of Rideal and Taylor’s book, published in
1926, biocatalysts were introduced in
the chapter “Colloidal Catalysts” together
with colloidal metals, because these two
possessed certain characteristics in
common, for example, drastic sensitivity
to poisons (inhibitors).[3] Moreover, the
metal colloids, which nowadays are fash-
ionably called nanoparticles, were, due
to their resemblance to biocatalysts,
termed “inorganic ferments.”[4] This
idiom, introduced by Bredig and M�ller
von Berneck, was probably the first
example of so-called biomimicry in the
field of catalysis, which later developed
into a general approach to new chemical
catalysts.
In the following decades, the gap be-
tween enzymes and ordinary catalysts
seemed to grow. The nature of enzymes
and their catalytic behavior remained a
mystery for much of the intervening
time and chemists simply left biocataly-
sis to the biologists. For chemical
engineers, enzymes were also of no
great interest, because implementation
of eco-friendly “green” technologies,
such as biocatalysis, was not the main
concern for production at that time. In
contrast, chemical catalysis, thanks to
enormous industry-driven development,
had already entered its “golden age” and
become an indispensable part of
chemical engineering.
A significant breakthrough in the field
of biocatalysis came in the late 1950s,
when the first three-dimensional enzyme
structure was resolved with the help of
X-ray analysis. The determination of spa-
tial configuration of enzymes and their
complexes with substrates and inhibitors
was an important milestone, which gave
an important insight into what makes
biocatalysts tick. Moreover, nothing
“miraculous” was found! Enzymes were
merely proven to be irregular organic
polymers, whose catalytic action does
not contradict the established chemical
theories. It became evident that rate ac-
celeration in enzymatic reactions results
from the same covalent or noncovalent
molecular interactions, which are in-
volved in regular chemical catalysis and
which serve the same goal—to stabilize
the transition state.[5] It was also found
that bio- and chemocatalysts often cata-
lyze the same reactions and sometimes
even have analogous structures
(Scheme 1 a). Moreover, both types of
catalysts, irrespectively of their nature,
compulsively obeyed fundamental ther-
modynamic principles, for example, shift-
ing the reaction equilibrium by applying
an excess of one reagent or by removing
one of the products (Scheme 1 b).
However, despite all of these dis-
closures, biocatalysts were still not fully
adopted into the “catalyst family”, be-
cause they also displayed some peculiari-
ties. Most intriguing was the beauty of
the enzymes’ molecular design, in which
every atom, positioned precisely in the
space called the active center, plays its
own role in the catalytic transformation
(Figure 3). This feature, now known as
multicentered catalysis, distinguished en-
zymes from the mostly single-centered
man-made catalysts, in which only a
single atom was responsible for the
reactant binding and transformation.[6, 7]
Another remarkable characteristic that
differentiated enzymes from chemo-
catalysts was their approach to enantio-
complementary reactions, which yield
the same product but with opposite
stereoconfiguration. In chemocatalytic
reactions, the switch of a reaction to the
opposing enantiomer is usually accom-
plished by using the mirrored form of a
catalyst (chiral ligand), such as (R)- and
(S)-BINOLAM for the cyanohydrine reac-
tion (Scheme 2). In contrast, the scaffolds
of enantiocomplementary enzymes
Scheme 1. Chemo- and biocatalysts often catalyze the same chemical reactions and obey the same
thermodynamic principles: a) Close analogy between the structures of manmade and natural catalyst
used for the epoxidation of olefins; b) shifting reaction equilibrium by removal of acetone in transfer
hydrogenation catalyzed by aluminum alkoxide or by alcohol dehydrogenase (ADH).
Figure 3. The hydrolysis of amides in the active site of a-chemotrypsin illustratesthe principle of multi-
centered catalysis, which distinguishes enzymes from most manmade catalysts.
104 www.chemcatchem.org � 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemCatChem 2010, 2, 103 – 107
R. Yuryev and A. Liese
www.chemcatchem.org
existing in nature are not related as true
mirror images, as is the case for the
hydroxynitrile lyases used in the cyano-
hydrine reaction (Scheme 2), although in
some cases the enzyme active sites
indeed functionally mirror each other.[8]
In the 1980s, the emergence of
another key technology—genetic engi-
neering—opened new horizons for bio-
catalysis. It became possible to modify
the arrangement of atoms in enzymes,
tuning in this way their catalytic proper-
ties. This crucial advancement initiated
the metamorphosis of biocatalysis from
fundamental science into cutting edge
technology for the manufacturing of
chemicals—industrial biotechnology.
The main benefits offered by enzymes
were their extraordinary activity, selec-
tivity, and “greenness.” Indeed, the
turnover frequencies for biocatalysts are
usually in the range 10–10 000 s�1, com-
pared to 1–10 s�1 or less for most chemi-
cal catalysts.[9] The absolute champion in
this regard is probably the enzyme
called catalase, which decomposes a
phenomenal 107 molecules of hydrogen
peroxide in its active site within one
second.[10] The regio- and enantioselec-
tivity of biocatalysts quickly led to their
use in the manufacturing of fine
chemicals, including pharmaceuticals,
agrochemicals, and their intermediates,
where the implementation of biotrans-
formations could significantly decrease
the number of required production
steps, reduce associated waste genera-
tion, and thus minimize fabrication
costs.[11] For instance, the chemical
synthesis of cortisone, a steroidal drug
for the treatment of rheumatoid arthritis,
developed by E. Merck (Darmstadt, Ger-
many), consisted of 31 steps and was
economically very ineffective: 615 kg of
deoxycholic acid was required to obtain
1 kg of cortisone acetate that resulted in
a high product end price ($200 per
gram). With introduction of a biocatalytic
step comprising hydroxylation of proges-
terone to 11a-hydroxyprogesterone by
the whole-cell biocatalyst Rhizopus
arrhizus, the synthesis of cortisone was
so simplified that its price could be
reduced to $6 per gram (Figure 4).[12]
In later years, industrial biotechnology
even entered the field of bulk chemicals
synthesized on a scale greater than
1000 tons per year, which was previously
considered the preserve of classical
chemical catalysis. Production of acryl-
amide by Mitsubishi Rayon is a well-
known example that illustrates this ten-
dency.[13, 14] In this process, which runs on
scales up to 50 000 tons per year, acrylo-
nitrile is hydrated by nitrile hydratase
from Rhodococcus rhodochrous in aque-
ous solution at 0–10 8C with greater than
99.9 % yield and selectivity (Scheme 3).
Such a biotransformation is environmen-
tally friendly because of its low E factor
(kgwaste/kgproduct)
[14] and ambient reaction
conditions. In contrast, the conventional
chemical process, in which acetonitrile is
hydrated over Raney copper at 80–
120 8C with 60–80 % conversion and
96 % selectivity, requires high energy
input, leading to CO2 emissions, and pro-
duces large quantities of toxic waste.
Moreover, chemically obtained acryl-
amide is contaminated with traces of
copper ions, which need to be removed.
Not surprisingly, nowadays practically all
acrylamide worldwide is produced via
the enzymatic route.[14]
Presently the alignment of enzymes
with chemical catalysts does not raise
Scheme 2. Enantiocomplementary catalysts for cyanohydrine reaction: (R)- and (S)-BINOLAM ligands vs.
hydoxynitrile lyases from Hevea brasiliensis (HbHNL) and Prunus amygdalis (PaHNL).
Figure 4. The economic impact of biocatalysis in the synthesis of cortisone.
Scheme 3. Mitsubishi Rayon process for
acrylamide illustrates application of industrial
biotechnology in the production of bulk
chemicals.
ChemCatChem 2010, 2, 103 – 107 � 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemcatchem.org 105
VIEWPOINTSBiocatalysis: The Outcast
www.chemcatchem.org
any doubts among chemists and chemi-
cal engineers. Nearly every modern mon-
ograph dealing with industrial or applied
catalysis includes a chapter, albeit often
a brief chapter, about biocatalysis. The
problem, however, remains that enzymes
do not fit into the historically arisen
“homogeneous/heterogeneous” catalyst
classification. Some people regard
enzymes as homogeneous catalysts, as
they are active in solution, whereas
others regard them as heterogeneous
because they are much bigger than
most of their substrates, as in hetero-
geneous catalysis, and the reaction envi-
ronment at the enzyme’s active site can
be totally different from the surrounding
(solvent) environment, unlike that in
homogeneous catalysis.[14] Even with
immobilized enzymes or whole-cell bio-
catalysts the situation is not as clear as it
first seems. For example, are enzymes
entrapped in gel or cross-linked enzyme
aggregates (CLEA)[15] heterogeneous?
The answer would definitely be “yes”, if
these systems were examined on the
macroscale, where the phase boundaries
are clearly visible. However, on the nano-
scale the phase boundaries blur because
solvent molecules easily penetrate into
these three-dimensional polymeric net-
works, and the “homogeneous/heteroge-
neous” differentiation loses its meaning.
It is worth noting that a similar classifica-
tion problem also occurs in the field of
chemical catalysis, when the traditional
macroscopic catalyst classification is
transferred to the nanoscale, resulting in
such confusing descriptions as “hetero-
genized homogeneous,” “homogenized
heterogeneous,” “quasi-homogeneous,”
or “multiphase homogeneous”, which
are frequently used today to describe
novel types of catalytic systems. Of
course, for a practitioner who thinks in
macroscale categories, this dilemma is
not of a great concern. From this point
of view, it seems preferable to apply the
generally adopted application-driven
classification of catalysts (Figure 1) as it
already hints at potential process design.
For example, “heterogeneous” prompts
one to think of solid catalysts, and there-
fore of packed bed reactors. “Homoge-
neous” in turn, indicates fluid systems
and thus stirred tank reactors. “Biocataly-
sis,” meanwhile, brings to mind green
chemistry and hints at ambient reaction
conditions. For a scientist, such inconsis-
tency without any deeper considera-
tions, would be irritating at the very
least and should be resolved!
From a bioscientist’s perspective, a
plausible approach to solving this dilem-
ma is to classify catalysts on the nano-
scale according to their origin (Figure 1).
On this account, one may divide catalysis
into two equal domains—chemo- and
biocatalysis. The classification criterion in
this case is whether a catalyst executes
its catalytic duties in vivo or not. Accord-
ing to this classification, enzymes are
single representatives of biocatalysts, be-
cause to date they are the only known
substances that catalyze metabolic reac-
tions in living organisms. From this point
of view, whole cells (living, resting, or
dead) are not regarded as a separate
class of biocatalysts because, in principle,
they are nothing more than conglomer-
ates of enzymes. However, in view of
applications, whole cells and enzymes
should be considered as separate classes
(Figure 2) because they are very distinct
in many technical aspects, such as the
addition of nutrients, aeration, biomass
growth, membrane transport, or cofactor
recycling. Chemocatalysis can be further
subdivided into three subcategories, two
of which, inorganic and organometallic
catalysis, are synonymous with the
modern semantics of heterogeneous
and homogeneous catalysis. Typical het-
erogeneous catalysts are inorganic solids
such as metals, metal oxides, and metal
sulfides,[16] whereas organometallic com-
pounds are widely used in homogene-
ouscatalysis.[17] The third subcategory,
organocatalysis, includes all metal-free
organic catalysts of both low and high
molecular weight. Discovered in the
1980s, catalytic RNAs (“ribozymes”)[18]
and antibodies (“abzymes”)[19] fall into
this division, since these biopolymers, al-
though synthesized by living organisms,
do not exhibit catalytic activity in vivo. If
one were to classify a biocatalyst as any
catalytic species produced in vivo, one
would also need to consider amino
acids, saccharides, and even some
biominerals as biocatalysts.
Origin-based catalyst classification is
not a new phenomenon; it has already
been implicitly expressed in a number of
works in which the term “chemocataly-
sis” appears as a counterpart to biocatal-
ysis.[20] However, this classification has,
unfortunately, a weak point: it relies on
the definition of “life”. Which systems
should be considered as “living”? Cur-
rently, there is no satisfactory answer to
this seemingly banal question, but it is
intuitively believed that there is a border
separating the six kingdoms of life from
the “kingdom of the nonliving” and that
this delimitation has not yet been
crossed. That is to say, to date no-one
has managed to effect biogenesis in a
test tube. It is, however, generally ac-
cepted that catalysis played a crucial role
during the evolution of the first primitive
organism on the prebiotic Earth[21] and
there is no reason to deny its potential
significance in the creation of simple
artificial “living” systems hereafter. Con-
temporary trends in the fields of bio-
and chemocatalysis reveal that both of
these domains are moving towards the
boundary that separates them (Figure 5).
Chemocatalysts are becoming more
“bio” by mimicking biocatalysts in size
and mechanism. For instance, the organ-
ometallic catalysts enlarged by their an-
choring to dendrimers (“dendrizymes”)[22]
or soluble polymers (“chemzymes”)[23]
imitate enzymes in size, as Bredig’s
aforementioned “inorganic ferments” do,
whereas inorganic redox molecular
sieves (“mineral enzymes” or “zeo-
zymes”)[24] replicate the catalytic cavity of
enzymes. More ambitious examples of
artificial enzymes are “synzymes”,[25]
which mimic the multicentered catalytic
mechanism of biocatalysts. On the other
side of this boundary, enzymes are be-
coming ever more “artificial”. Thanks to
protein engineering, the structure-based
rational design of novel biocatalysts is
today a reality. It is now even possible to
incorporate unnatural amino acids into
enzyme structures[26] or to build artificial
metabolic networks in vitro,[27] illustrating
how quickly biocatalysis has entered the
newly emerging field of synthetic
biology.
The proposed origin-based classifica-
tion should not be viewed as an attempt
to reclassify the field of catalysis ; reclassi-
fication simply makes no sense because
no universal classification system is
possible. Every suggested system of
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R. Yuryev and A. Liese
www.chemcatchem.org
classification serves a certain purpose,
depending on the selected classification
criteria. For example, if classification is
based on the macroscopic behavior of
catalysts, a variety of feasible classifica-
tion systems may be conjured up, for
example, homogeneous/heterogeneous
(not homogeneous/heterogeneous/bio!),
or gaseous/liquid/solid, or stable/un-
stable, or toxic/nontoxic, which can be
very useful in certain applications. The
origin-based bio/chemo classification
also serves its purpose. Firstly, it shows
that biocatalysis should not be treated
as an outcast, but rather as an equal
member of the catalysis family. Secondly,
it concentrates attention on the borders
separating chemo- and biocatalysis, or in
other words, it asks the question: “Is arti-
ficial life possible?” To answer that ques-
tion positively would mean to merge
both bio- and chemocatalysis into one
category.
Advances in merging bio- and chemo-
catalysis are of course not possible with-
out understanding catalytic systems on
an atomic level. Molecular modeling is
nowadays an indispensable research tool
for catalyst tailoring,[14, 28] providing also
a basis for the unification of all branches
of catalysis. Indeed, computational
chemistry treats all catalysts on the same
level, regardless of their “bio” or
“chemo” origin. However, despite recent
progress in computational techniques,
which has allowed new insights into cat-
alytic phenomena, it is still far from
reaching the ultimate goal of catalysis
unification. Therefore, the origin-based
catalyst classification system must
remain current until the first “artificial
bug” says “hello world!” from the lab
bench.
Keywords: biocatalysis · biomimetic
synthesis · heterogeneous catalysis ·
homogeneous catalysis · organocatalysis
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Received: May 4, 2009
Revised: July 14, 2009
Published online on November 5, 2009
Figure 5. Bio- and chemocatalysis are converging on the boundary that separates them. Ellipses depict
chemocatalysts that mimic biocatalysts in size or mechanism.
ChemCatChem 2010, 2, 103 – 107 � 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemcatchem.org 107
VIEWPOINTSBiocatalysis: The Outcast
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