Science - USA (2021-07-16)

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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

antibacterial immunity.

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

REFERENCES AND NOTES

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2. C. F. Nathan et al., N. Engl. J. Med. 315 , 6 (1986).


3. G. Karupiah et al., Science 261 , 1445 (1993).


4. R. Gaudet et al., Science 273 , eabf8113 (2021).


5. K. J. Tracey, Nature 420 , 853 (2002).


6. S.-Y. Zhang et al., Curr. Opin. Immunol. 59 , 88 (2019).


7. Y. Belkaid, J. A. Segre, Science 346 , 954 (2014).


8. H. L. Cash, C. V. Whitham, C. L. Behrendt, L. V. Hooper,
   Science 313 , 1126 (2006).


9. S. P. Rosshart et al., Science 365 , eaaw4361 (2019).


10. D. Bogunovic et al., Science 337 , 1684 (2012).


11. M. Walch et al., Cell 157 , 1309 (2014).


12. S. Fanucchi et al., Immunity 54 , 32 (2021).


13. J. Bustamante, S. Boisson-Dupuis, L. Abel, J.-L.
    Casanova, Semin. Immunol. 26 , 454 (2014).


14. International Chronic Granulomatous Disease
    Cooperative Study Group, N. Engl. J. Med. 24 , 509 (1991).


15. C. Schaub et al., J. Biol. Chem. 295 , 13138 (2020).

ACKNOWLEDGMENTS

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.

10.1126/science.abj5637

ZEOLITE CHEMISTRY

Bioinspired methane oxidation

in a zeolite

By Susannah L. Scott

F

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.

Email: [email protected]

Radical rebound

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.

Radical escape

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

II

FeIV

2 N 2 O

N 2 O

N 2 N^2

2

O

CH 4

•CH 3

•CH 3

CH 3

•CH 3

CH 4

Complete turnover

with rebound in cage

(CHA)

Stoichiometric

reaction with radical

cage escape (*BEA)

CaptureCapture

No reactionNo reaction

H abstractionH abstraction

Cage escape

FeIII

HO

FeIII

HO FeIII

O

H 3 C

FeIII

HO

FeIII

HO

FeII

HO

FeIV

O

FeIV

O

FeIV

O FeIV

O

ReleaseRelease

OxidationOxidation

OxidationOxidation

ReboundRebound

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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