SCIENCE sciencemag.org 16 JULY 2021 • VOL 373 ISSUE 6552 277
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by APOL3 ( 4 ). Perhaps such susceptibilities
reflect, at least in part, a failure to induce
APOL3. Administration of IFN-g reduces the
incidence of infections in people with chronic
granulomatous disease ( 14 ), without correct-
ing their leukocytes’ defect in production of
reactive oxygen species. Perhaps the mecha-
nisms of protection include induction of apo-
lipoproteins and GBPs.
Future research should address which
cells express APOL3 and the other IFN-g–
induced, intracellular apolipoproteins in
vivo, and what functions are served by each.
Perhaps one of them helps kill intracellular
Trypanosoma cruzi, the agent of Chagas dis-
ease, given that circulating apolipoprotein
L1 (APOL1) kills extracellular Trypanosoma
brucei, which causes sleeping sickness ( 15 ).
Some of the bacteria that are susceptible to
destruction by APOL3 plus GBP1 are none-
theless pathogenic. Perhaps they express
counter-mechanisms, as is the case with T.
brucei that resist lysis by APOL1 ( 15 ). It will
be interesting to determine how and to what
extent GBP1 and APOL3 discriminate be-
tween bacterial membranes and the host’s
own bacteria-like mitochondrial membranes.
Damage to mitochondria can increase their
release of reactive oxygen species, which
could further contribute to IFN-g–induced
Interferons were identified as proteins
that induce an antiviral state in cells con-
sidered to lie outside the immune system.
Now, IFNg from innate and adaptive lym-
phocytes can instruct such cells to express
proteins that kill bacteria within them. This
reminds us not to let the affiliation given
to cell types constrain our understanding of
their functions. Just as cells of the conven-
tional immune system contribute to homeo-
stasis in every organ, so can other cells in
every organ contribute to immunity. j
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C.N. is supported by the National Institutes of Health, the
Bill & Melinda Gates Foundation, and the Milstein Program in
Chemical Biology and Translational Medicine.
Bioinspired methane oxidation
in a zeolite
By Susannah L. Scott
undamental advances have enhanced
our understanding of how to acti-
vate the very stable C–H bonds in
methane ( 1 ), but its conversion into
useful chemicals such as methanol
through simple, cost-effective, modu-
lar processes is still an unsolved problem
( 2 ). Living systems oxidize hydrocarbons,
including methane, at near-ambient tem-
peratures using enzymes that contain
Earth-abundant metals (typically iron and
copper). However, their electronic struc-
tures favor single-electron transfers that
generate highly reactive radical intermedi-
ates ( 3 ). Escape of these radicals from the
vicinity of an enzyme’s active site must be
scrupulously avoided to prevent damage to
nearby biological structures. On page 327 of
this issue, Snyder et al. ( 4 ) demonstrate how
one of nature’s strategies can be mimicked
in an iron-containing zeolite that promotes
radical formation and capture in rapid suc-
cession. This gating of molecular transport
regenerates the active sites while limiting
the propensity of radicals to deactivate ac-
tive sites located in other zeolite pores.
Enzymes functionalize normally unreac-
tive saturated hydrocarbons such as methane
selectively by using a “rebound” mechanism
( 5 ). In heme-based P450 and peroxidase en-
zymes, as well as nonheme iron dioxygen-
ases, a highly oxidized iron site (Fe=O, ferryl)
abstracts a hydrogen atom from the organic
molecule and creates an organic radical. The
oxygen atom becomes a hydroxyl (Fe-OH)
that must recapture the organic radical by
forming a stable C–O bond before the radi-
cal can diffuse away. Thus, the environment
around the active site of an enzyme deter-
mines the reaction outcome by restricting
Molecular-sized iron-containing cages control
conversion of methyl radicals into methanol
Department of Chemical Engineering and Department
of Chemistry and Biochemistry, University of California,
Santa Barbara, Santa Barbara, CA 93106, USA.
The aperture of a CHA cage is smaller than the diameter
of a methyl radical (3.9 Å). The radical reacts with the
ferric hydroxyl (FeIIIOH) site, releases methanol, and
regenerates the ferrous ion.
In *BEA, the methyl radical diffuses readily along the
zeolite channel, whose diameter is larger than the
radical. It reacts with another ferryl ion to create two
inactive ferric sites, rather than form methanol.
CH 3 OH
FeII FeII Fe
2 N 2 O
N 2 O
N 2 N^2
with rebound in cage
reaction with radical
cage escape (*BEA)
No reactionNo reaction
H abstractionH abstraction
H 3 C
H abstractionH abstraction
Different rebounding abilities
The fate of methyl radicals in zeolites depends on the cage aperture size. In microporous zeolites such as
chabazite (CHA) and beta (*BEA), extra-framework ferrous (FeII) ions are oxidized to ferryl (FeIVO) ions that
can abstract a hydrogen atom from a methane molecule.
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