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Molybdenum. 1900 – discovered in plant ashes 1930 - azotobacter (N2 fixer) growth requirement for Mo 1940 – established as essential micronutrient for plants 1950 - [Mo] affected rat XO activity; [Mo]~ [flavin] Mo associated with aldehyde oxidase in rabbit livers

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slide1

Molybdenum

1900 – discovered in plant ashes

1930 - azotobacter (N2 fixer) growth requirement for Mo

1940 – established as essential micronutrient for plants

1950 - [Mo] affected rat XO activity; [Mo]~ [flavin]

Mo associated with aldehyde oxidase in rabbit livers

1960 - Mo crucial to N-cycle

MoS

The only 4d metal essential to Life

slide2

Table 1. The Oxomolybdenum Enzymes (R. Hille, Chem. Rev. 1996)

The Xanthine Oxidase Family (LMoOS-Possessing Enzymes)

enzyme source subunits cofactora

xanthine oxidase cow’s milkb R2 MPT

xanthine dehydrogenase chicken liverc R2 MPT

rat liverd R2 MPT

Micrococcus lactyliticuse

Drosophila melanogasterf R2 MPT

Chlamydomonas reinhardtiig

humanh R2 (MPT)

aldehyde oxidase rabbit liveri R2 (MPT)

humanj R2 (MPT)

cowk R2 (MPT)

aldehyde oxidoreductase (dehydrogenase) Desulfovibrio gigasl R2 MCD

Acetobacter polyoxogenesm

formate dehydrogenase Alcaligenes eutrophusn Râçä

Methylosinus trichosporumo R2â2ç2ä2

CO dehydrogenase (oxidoreductase) Pseudomonas carboxydovoransp R2â2ç2

Pseudomonas carboxydoflavaq R2â2ç2 MCD

Oligotropha carboxidovoransr R2â2ç2 MCD

quinoline-2-oxidoreductase Pseudomonas putida s R2â2ç2 MCD

Rhodococcus sp. B1t R2â2ç2 MCD

Comamonas testosteroni 63u R2â2ç2 MCD

isoquinoline 1-oxidoreductase Pseudomonas diminutav Râ MCD

quinoline-4-carboxylate-2-oxidoreductase Agrobacterium sp. 1Bw R2â2ç2 MCD

quinaldine-4-oxidoreductase Arthrobacter sp.x R2â2ç2 MCD

quinaldic acid 4-oxidoreductase Serratia marcescensy

Pseudomonas sp. AK-2z Râ

nicotinic acid hydroxylase (dehydrogenase) Clostridium barkeriaa,ab R2

Bacillus niaciniac R2â2ç2

Arthrobacter oxidansad Râç

6-hydroxynicotinate hydroxylase Bacillus niaciniac Râç

nicotine dehydrogenase Arthrobacter oxidansad Râç

Arthrobacter nicotinovoransae

picolinate hydroxylase Arthrobacter picolinophilusaf R2â2ç2 MCD

(2R)-hydroxycarboxylate oxidoreductase Proteus vulgarisag

The Sulfite Oxidase Family (LMoO2-Possessing Enzymes)

sulfite oxidase bovine liverah R2 MPT

chicken liverai R2 MPT

rat liveraj R2 MPT

humanak R2 MPT

Thiobacillus novellusal R

nitrate reductase (assimilatory) Neurospora crassaam R2 MPT

spinachan R2 MPT

Chlorella vulgarisao R4 MPT

The DMSO Reductase Family (L2MoX-Possessing Enzymes)

DMSO reductase Rhodobacter sphaeroidesap R MGD

Rhodobacter capsulatus aq R MGD

Escherichia coli ar Râç MGD

biotin-S-oxide reductase Escherichia colias

trimethylamine-N-oxide reductase Escherichia coliat R2

nitrate reductase (dissimilatory) Escherichia coli (NarGHI)au Râç MGD

Escherichia coli (NarZYV)av Râç MGD

Escherichia coli (FdoGHI)aw Râç MGD

Paracoccus denitrificans (NapABCD)ax Râçä

Haloferax volcaniiay

formate dehydrogenase Escherichia coli (FdhF)az R MGD

Escherichia coli (FdnGHI)ba Râç MGD

Escherichia coli (FdoGHI)bb Râç MGD

Methanobacterium formicicumbc (XdS) Râç MGD

Wollinella succinogenesbd Râç

polysulfide reductase Wolinella succinogenesbe Râç MGD

arsenite oxidase Alcaligenes faecalisbf R MCD

formylmethanofuran dehydrogenase) Râçä(ú) MGD, MAD, MHD

Methanosarcina barkeribh MGD

Unclassified Molybdenum-Containing Enzymes

pyridoxal oxidase Drosophila melanogaster

chlorate reductase Proteus mirabilis

tetrathionite reductase Proteus mirabilis

xanthine dehydrogenase Clostridium sp

pyruvate:ferredoxin oxidoreductase Archaeoglobus fulgidus

pyrogallol transhydroxylase Pelobacter acidigallici

2-furoyl-CoA dehydrogenase Pseudomonas putida

slide3

Locating the Molybdenum Cofactor

All mammals require

molybdenum enzymes

Sulfite Oxidase

SO32- + H2O

SO42- + 2H+ + 2e-

All plants require the

molybdenum enzyme

Nitrate Reductase

NO3- + 2H+ + 2e-

NO2- + H2O

Mo(4+) + X-O + 2H+ Mo(6+) + X + H2O

slide4

NO2-

N2

Nitrate

reductase

nitrogenase

Nitrogen- cycle

NO3-

NH3

polysulfide

reductase

SH2

CH4

Sx

Carbon- cycle

Sulfur- cycle

CO2

CH3CO2-

(CH3)2S

(CH3)2SO

DMSO

reductase

slide5

Table 1. The Oxomolybdenum Enzymes

(R. Hille, Chem. Rev. 1996)

The Xanthine Oxidase Family (LMoOS-type)

enzyme source cofactor

xanthine oxidase cow’s milk MPT

xanthine dehydrogenase chicken liver MPT

rat liver MPT

Drosophila melanogaster MPT

human MPT)

aldehyde oxidase rabbit liver MPT

human MPT

cow MPT

aldehyde oxidoreductase (dehydrogenase) Desulfovibrio gigas MCD

formate dehydrogenase Alcaligenes eutrophus

CO dehydrogenase (oxidoreductase) Pseudomonas carboxydovorans

quinoline-2-oxidoreductase Pseudomonas putida MCD

isoquinoline 1-oxidoreductase Pseudomonas diminuta MCD

quinoline-4-carboxylate-2-oxidoreductase Agrobacterium sp MCD

quinaldine-4-oxidoreductase Arthrobacter sp. MCD

quinaldic acid 4-oxidoreductase Serratia marcescens

Pseudomonas sp. AK

nicotinic acid hydroxylase (dehydrogenase) Clostridium barkeriaa,

6-hydroxynicotinate hydroxylase Bacillus niaciniac

nicotine dehydrogenase Arthrobacter oxidansa

The Sulfite Oxidase Family (LMoO2-type)

enzyme source cofactor

sulfite oxidase bovine liver MPT

chicken liver MPT

rat liver MPT

human MPT

Thiobacillus novellus

nitrate reductase (assimilatory) Neurospora crassa MPT

spinach MPT

Chlorella vulgari MPT

The DMSO Reductase Family (L2MoX-type)

DMSO reductase Rhodobacter sphaeroides MGD

biotin-S-oxide reductase Escherichia colia

trimethylamine-N-oxide reductase Escherichia colia

nitrate reductase (dissimilatory) Escherichia coli (NarGHI) MGD

formate dehydrogenase Escherichia coli (FdhF) MGD

polysulfide reductase Wolinella succinogene MGD

arsenite oxidase Alcaligenes faecalisb MCD

formylmethanofuran dehydrogenase) MGD, MAD, MHD

Unclassified Molybdenum-Containing Enzymes

pyridoxal oxidase Drosophila melanogaster

chlorate reductase Proteus mirabilis

tetrathionite reductase Proteus mirabilis

xanthine dehydrogenase Clostridium sp.

pyruvate:ferredoxin oxidoreductase Archaeoglobus fulgidus

pyrogallol transhydroxylase Pelobacter acidigallici

2-furoyl-CoA dehydrogenase Pseudomonas putida

slide6

The Generic Molybdenum Cofactor

MAD

MGD

MCD

MPT

There’s not only one, but a family of Moco’s

slide7

dithiolene

pterin

Why molybdopterin?

Mo

slide8

Table 1. The Oxomolybdenum Enzymes

(R. Hille, Chem. Rev. 1996)

The Xanthine Oxidase Family (LMoOS-type)

The Sulfite Oxidase Family (LMoO2-type)

The DMSO Reductase Family (L2MoX-type)

Used to be classed with XO

b/c structural similarity.

Unique Mo enzyme with a 2nd metal, Cu

slide9

Table 1. The Oxomolybdenum Enzymes

(R. Hille, Chem. Rev. 1996)

The Xanthine Oxidase Family (LMoOS-type)

Xanthine Oxidase/Dehydrogenase

- in mammalian milk but >50% de-Mo

- in liver: purine metabolism (gout)

- implicated in heart damage (ROS form’n)

The Sulfite Oxidase Family (LMoO2-type)

Nitrate Reductase

- in all plants

- assimilatory form (plants, fungi, algae)

Sulfite Oxidase

- most critical for humans

- detoxification of sulfite

- also has role in S-metabolism,

from Cys  Met   SO32-  SO42-

The DMSO Reductase Family (L2MoX-type)

- all bacterial or from archea

- many in respiration using specific e- acceptors

- recall DMSOR in cloud formation ….

- simplest Mo-enzymes: w/o other cofactors

slide10

Table 1. The Oxomolybdenum Enzymes

(R. Hille, Chem. Rev. 1996)

The Xanthine Oxidase Family (LMoOS-type)

- in mammalian milk but >50% de-Mo

- in liver: purine metabolism (gout)

- implicated in heart damage (ROS form’n)

The Sulfite Oxidase Family (LMoO2-type)

Nitrate Reductase

- in all plants

- assimilatory form (plants, fungi, algae)

NO3- + 2H+ + 2e-  NO2- + H2O

Sulfite Oxidase

- most critical for humans

- detoxification of sulfite

- also has role in S-metabolism,

from Cys  Met   SO32-  SO42-

SO32- + H2O  SO42- + 2H+ + 2e-

The DMSO Reductase Family (L2MoX-type)

- all bacterial or from archea

- many in respiration using specific e- acceptors

- recall DMSOR in cloud formation ….

- simplest Mo-enzymes: w/o other cofactors

slide11

Root nodules

formed

by

Rhizobium bacteria

living symbiotically

through

nitrogen fixation.

slide13

Tobacco plants (Arabidopsis thaliana)

Nitrate Nitrite Proteins

nitrate nitrite

Healthy

(wild type)

Sick

(mutant)

All plants require

Assimilatory

Nitrate Reductase

slide15

Introduction

Repairing the Molybdenum Cofactor

Baby Z Cured of Rare Disease in 3 Days

Orphan Drug Treatment Used Only on Mice to Get Hearing Before FDA

By SUSAN DONALDSON JAMES, Nov. 9, 2009

(Southern Health/AFP/Getty Images)

Baby Z had a one in a million chance of developing a rare metabolic disorder called molybdenum cofactor deficiency and zero chance of avoiding the inevitable death sentence that comes with it.

The Australian girl had a seemingly normal birth in May 2008 but, within hours, she began having multiple seizures -- as many as 10 an hour -- as sulfite build-up began to poison her brain. With the clock ticking, doctors who treated Baby Z gained approval from the hospital\'s ethics board and a family court to use the experimental treatment.

The drug -- cPMP, a precurser molecule made from E. coli bacteria -- was airlifted on ice from the lab of German professor Guenter Schwarz and, within three days, it worked.

University of Arizona, Tucson, October 2010

Worldwide, there are only about 50 cases of molybdenum cofactor, or sulfite oxidase deficiency, mostly in Europe and in the United States, according to the National Institutes of Health. Molybdenum, like other organic metals, is essential for the human body. Its cofactor is a small, complicated molecule that acts as a carrier to help the metal interact with proteins and enzymes so they can function properly. When the cofactor is missing, toxic sulfite builds and begins to cause degeneration of neurons on the brain and eventually death.

"This was the first time I ever saw this," said Dr. Alex Veldman, the Monash neonatologist who headed up Baby Z\'s treatment. "It\'s very funny, now I am regarded a world specialist but I can tell you that before last May, I couldn\'t even spell it."

slide17

MRI of brain of deceased baby

with Sulfite Oxidase Deficiency

MRI of healthy brain

slide18

The baby died because this reaction didn’t happen:

SO32- + H2O ---> SO42- + 2H+ + 2e-

Sulfite Sulfate

S4+ S6+

The baby has a genetic defect in the enzyme

that catalyzes this reaction.

Babies with this genetic disease die within hours.

The enzyme is Sulfite Oxidase.

You have it in your liver.

slide19

Review the terms:

Oxidation SO32- + H2O ---> SO42- + 2H+ + 2e-

half reactionS4+ in Sulfite S6+ in Sulfate

Reduction Mo6+ + 2e- ---> Mo4+

half reaction

Net redox reaction

SO32- + H2O + Mo6+ ---> SO42- + 2H+ + Mo4+

Is this reaction spontaneous?

slide20

Caroline Kisker

Würzburg, Germany

Protein crystallographer

X-ray structure of chicken liver Sulfite Oxidase

Kisker, Enemark

slide26

Similar cycles can be devised for

Sulfite Oxidase

and Nitrate Reductase

SO32- + H2O ---> SO42- + 2H+ + 2e-

Sulfite Sulfate

S4+ S6+

NO3- + 2H+ + 2e- ---> NO2- + H2O

Nitrate Nitrite

N5+ N3+

slide27

DMS

CH3SO3-

cloud nucleation sites

hn, photo-oxidation

DMS

(CH3)2S(CH2)2CO2-

from algae

DMSO Reductase

DMSO

Environmental impact of DMSOR and the smell of the ocean

slide28

DMSOR Structure: Controversy #2

The first Mo enzyme X-ray structure: DMSO Reductase

Doug Rees, 1996

Doug Rees, Cal Tech

Protein crystallographer

Group Meeting Bryn Mawr College, October 2010

  • SURPRISE!!!!
  • 2 molydopterin ligands!
  • nucleoside termini on pterin
  • very long Mo-S bonds
slide29

DMSOR Structure: Controversy #2

The first look at molybdopterin was on a tungsten enzyme!

Hyperthermophilic TungstonEnzyme, Aldehyde Ferredoxin Oxidoreductase

Doug Rees et al., Science,1995

Group Meeting Bryn Mawr College, October 2010

  • SURPRISE!!!!
  • not the molydopterin ligand!
  • is that pyran ring actually right???
slide30

DMSOR Structure: Controversy #2

Will the real active site structure in DMSO Reductase please stand up?

Group Meeting Bryn Mawr College, October 2010

(S J N Burgmayer, in Progress in Inorganic Chemistry, 2004)

slide32

Hermann Schindelin, Würzburg, Germany

Protein crystallographer

DMSOR Structure: Controversy #2

1.3 Å X-ray Structure in DMSO Reductase (Schindelin)

Group Meeting Bryn Mawr College, October 2010

Inactive

form

Active form

What does it mean?

There are 2 superimposed structures.

(only one is inactive!)

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