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Journal of Inherited Metabolic Disease

, Volume 34, Issue 3, pp 671–676 | Cite as

Structural basis of fumarate hydratase deficiency

  • Sarah Picaud
  • Kathryn L. Kavanagh
  • Wyatt W. Yue
  • Wen Hwa Lee
  • Susanne Muller-Knapp
  • Opher Gileadi
  • James Sacchettini
  • Udo Oppermann
Open Access
Original Article
First Online:
Received:
Revised:
Accepted:

Abstract

Fumarate hydratase catalyzes the stereospecific hydration across the olefinic double bond in fumarate leading to L-malate. The enzyme is expressed in mitochondrial and cytosolic compartments, and participates in the Krebs cycle in mitochondria, as well as in regulation of cytosolic fumarate levels. Fumarate hydratase deficiency is an autosomal recessive trait presenting as metabolic disorder with severe encephalopathy, seizures and poor neurological outcome. Heterozygous mutations are associated with a predisposition to cutaneous and uterine leiomyomas and to renal cancer. The crystal structure of human fumarate hydratase shows that mutations can be grouped into two distinct classes either affecting structural integrity of the core enzyme architecture, or are localized around the enzyme active site.

An interactive version of this manuscript (which may contain additional mutations appended after acceptance of this manuscript) may be found on the SSIEM website at:http://www.ssiem.org/resources/structures/FH.

Keywords

Fumarate TCEP Fumarate Hydratase Leiomyomatosis Uterine Leiomyomata 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

FH

Fumarate hydratase

FHD

Fumarate hydratase deficiency

MCUL1

Multiple cutaneous and uterine leiomyomata

HLRC

Hereditary leiomyomatosis and renal cancer syndrome

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Introduction

Fumarate hydratase (FH) and succinate dehydrogenase are two integral enzyme components of the Krebs cycle, and besides their essential role in the TCA cycle, can act as tumour suppressors (King et al. 2006). The FH gene codes for fumarate hydratase (or fumarase; EC 4.2.1.2), which catalyzes the stereospecific, reversible hydratation of fumarate to L-malate. The FH gene localized at 1q42.1 codes for differentially processed, but sequence-wise identical cytosolic and mitochondrial forms. Whereas the mitochondrial enzyme is part of the TCA cycle, the cytosolic form is thought to utilize fumarate derived from different sources. Deficiency in FH activity causes an impaired energy production by interrupting the flow of metabolites through the Krebs cycle. Accumulation of fumarate is thought to competitively inhibit 2-oxo-glutarate dependent dioxygenases that regulate hypoxia inducible factor (HIF), thus activating oncogenic hypoxia pathways (Ratcliffe, 2007).

Due to their essential role in energy production, enzyme deficiencies result in early onset of severe encephalopathy (Kerrigan et al. 2000). Accordingly, autosomal recessive fumarate hydratase deficiency (FHD) caused by mutations in the FH gene results in fumaric aciduria, and common clinical features observed are hypotonia, failure to thrive, severe psychomotor retardation, seizures, facial dysmorphism and brain malformations. Interestingly, whereas homozygous FH mutations predispose to fumaric aciduria, several heterozygous FH mutations are known to be involved in the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomata (MCUL1) (Tomlinson et al. 2002). Affected individuals develop benign smooth muscle tumours of the skin, and females develop fibroids of the uterus. When co-existing with an aggressive form of renal cell carcinoma (papillary renal type II cancer or renal collecting duct cancer) it is also known as hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. In MCUL1/HLRCC germline mutations in FH are detected in the majority of the screened cases. To date, 107 variants have been described, of which 93 are thought to be pathogenic (Bayley et al. 2008). The most common types are missense mutations (57%), followed by frameshift and nonsense mutations (27%), as well as diverse deletions, insertions and duplications.

Here we present the crystal structure of human fumarase at 1.95 Å resolution and summarize structure-activity correlation between observed mutations and clinical phenotypes.

Materials and methods

Expression, purification & crystallization

DNA fragment encoding the fumerase domain of human FH (aa 44-510; GenBank entry 19743875) was subcloned into pNIC28-Bsa4 vector incorporating an N-terminal His6-tag. The plasmid was transformed into BL21(DE3)-pRARE, cultured in Terrific Broth at 37°C, and induced with 0.1 mM IPTG overnight at 18°C. Cells were homogenized in lysis buffer (50 mM K-phosphate pH 7.5, 500 mM NaCl, 1 mM TCEP), centrifuged to remove cell debris, and the supernatant was purified by Nickel affinity (HisTrap Crude FF) and size exclusion (HiLoad 16/60 Superdex S200) chromatography. Purified protein was concentrated to 12.6 mg/ml and stored in 10 mM HEPES pH 7.5, 150 mM NaCl, 5% (w/v) glycerol and 0.5 mM TCEP at -80°C. Crystals were grown by vapour diffusion at 20°C in sitting drops mixing 150 nl protein and 150 nl reservoir solution containing 20% (w/v) PEG 3350, 0.2 M sodium acetate, 10% (w/v) ethylene glycol and 100 mM Bis-Tris propane pH 7.5. Crystals were cryo-protected in mother liquor containing 25% (w/v) glycerol and flash-frozen in liquid nitrogen.

Data collection & structure determination

Diffraction data to maximum resolution of 1.95 Å were collected on beamline X10A at the Swiss Light Source, and processed using the CCP4 Program suite (CCP4, 1994). FH crystallized in the trigonal space group P3221 (a = 180.5 Å, b = 180.5 Å, c = 114.6 Å, α = 90o, β = 90o, γ = 120o) with four molecules in the asymmetric unit. The structure of FH was solved by molecular replacement with PHASER (McCoy et al. 2005), using the yeast fumerase structure as search model (PDB code 1YFM). Initial automated model building was performed with ARP/wARP (Perrakis et al. 1999). This is followed by cycles of iterative manual model building using COOT (Emsley & Cowtan 2004) and restrained refinement using REFMAC5 with TLS parameters (Murshudov et al. 1997). The final structure was deposited in the Protein Data Bank (www.rcsb.org) under accession code 3E04 (Table 1).
Table 1

X-ray data collection and refinement statistics

Data collection

 Space group

P3221

 a, b, c (Å)

188.5, 188.5, 114.6

 γ

120o

 Wavelength (Å)

1.000

 Resolution (Å)*

25.0 – 1.95 (2.06 – 1.95)

 Rmerge (%)*

0.141 (0.732)

 I/σI*

9.7 (2.0)

 Completeness (%)*

99.3 (96.8)

 Redundancy*

6.2 (5.0)

Refinement

 Resolution (Å)

41.27 – 1.90

 No. reflections

168629

 Rwork/Rfree (%)

19.7/24.4

 No. atoms

  Protein

13160

  Ligand/ion

12

  Water

655

 B-factors (Å2)

 

  Main-chain

24.88

  Side-chain and water

25.91

 RMS deviations

  Bond lengths (Å)

0.010

  Bond angles (°)

1.201

 PDB code

3E04 (doi: 10.2210/pdb3e04/pdb)

* Numbers in parentheses represent data in the highest resolution shell.

Results and discussion

Fumarases are divided into two distinct groups. Class I fumarases are iron-dependent iron-sulfur cluster containing, dimeric enzymes, whereas the class II enzymes, including human and other eukaryotic fumarases, are homotetrameric enzymes with a molecular mass of about 200 kDa. Class II fumarases are evolutionarily highly conserved enzymes, e.g. the pairwise identity between E. coli and human fumarase is about 60%. Every monomer exhibits a typical tridomain structure, with a central domain involved in subunit interaction, thus forming a typical bundle comprised of 20 α-helices (Fig. 1A). Previous crystallographic analyses have revealed two distinct sites (A and B) in E. coli fumarase that can bind carboxylic acids. Site A is formed from three different monomer chains and likely to be the catalytic site, whereas site B is thought to allosterically regulate activity (Rose and Weaver 2004).
Fig. 1

Ribbon/surface diagram of human fumarate hydratase illustrating the tetrameric assembly of class II fumarases. Molecular surface representation is used to convey the overall shape of each monomer as well as the tetrameric assembly. Each monomer has been coloured distinctively, to facilitate visualization. Two monomers are represented using semi-transparent surfaces, to highlight the fold (represented as ribbons). One of the active sites is highlighted in red, showing contribution of three distinct subunits. The figures were generated using the program ICM (www.molsoft.com)

A previous study correlated 27 distinct missense mutations to the E. coli fumarase structure (Alam 2005b), since then the list of mutations has doubled. To this end, 55 missense mutations in the human fumarase gene are now described. Here we correlate this updated list of mutations to fumarase deficiency, MCUL1 and HLRCC syndrome (Table 2) by using the human fumarase structure. Although not all of these novel mutations have been biochemically characterized, previous results suggest that FH activity is related to HLRCC (Alam 2005a), although other environmental or genetic factors likely play a role in the etiology of the disease. The clustering of mutational “hotspots” suggests enzyme activity relationships to phenotypic appearances. Figure 2 illustrates the clustering of FH mutations observed in FHD, MCUL1 and HLRCC. The large majority of mutations are located at evolutionarily highly conserved positions (Table 2) indicating that these mutations likely affect stability and/or activity of the enzyme. Two major clusters of mutations are observed; one is likely to affect structural integrity of the enzyme by interrupting inter or intrasubunit interactions (indicated in yellow in Fig. 2), whereas the other mutations are located around the active site and likely directly affect activity.
Table 2

Mutations observed in the human fumarase gene and association to disease. Abbreviations: CL: cutaneous leiomyoma; FHD: fumarate hydratase deficiency; HLRCC: hereditary leiomyomatosis and renal cell cancer; LCT: Leydig cell tumors; MCUL: multiple cutaneous and uterine leiomyomata; OMC: ovarian mucinous cystadenoma; RCC: renal cell carcinoma; STS: soft tissue sarcoma; UL: uterine leiomyomas; ULMS: uterine leiomyosarcoma

#

Mutation site

Mutated residue

Protein change

DNA change

Exon

Conservation

Localization

Reference

Phenotype

1

Arg51

Glu

R51E

c.152 G > A

2

Conserved

Surface

(Kiuru et al. 2002)

STS

2

Arg101

Pro

R101P

c.302 G > C

3

Semi-conserved

Surface

(Chan et al. 2005), (Heinritz et al. 2008)

HLRCC

3

Asn107

Thr

N107T

c.320A > C

3

Conserved

Active site

(Tomlinson et al. 2002), (Alam et al. 2005a), (Carvajal-Carmona et al. 2006)

MCUL, LCT

4

Ala117

Pro

A117P

c.349 G > C

3

Semi-conserved

Near active site

(Tomlinson et al. 2002)

MCUL

5

Leu132

Ser

L132S

c.395 T > C

4

Semi-conserved

Surface

(Wei et al. 2006)

HLRCC, reduced FH activity

6

His135

Arg

H135R

c.404A > G

4

Semi-conserved

Surface

(Chuang et al. 2005)

MCUL

7

Gln142

Lys

Q142K

c.424 C > A

4

Conserved

Near active site

(Badeloe et al. 2006)

MCUL

8

Ser158

Ile

S158I

c.473 G > T

4

Semi-conserved

Near active site

(Martinez-Mir et al. 2003)

MCUL

9

Arg160

Gly

R160G

c.478A > G

4

Conserved

Surface

(Wei et al. 2006)

MUCL, reduced FH activity

10

Pro174

Arg

P174R

c.521 C > G

4

Not conserved

Surface

(Alam et al. 2005b), (Zeng et al. 2006), (Pollard et al. 2005)

FHD

11

His180

Arg

H180R

c.539A > G

4

Semi-conserved

Active site

(Tomlinson et al. 2002), (Alam et al. 2005b)

MUCL

12

Gln185

Arg

Q185R

c.554A > G

4

Conserved

Active site

(Tomlinson et al. 2002)

MCUL

13

Ser187

Leu

S187L

c.560C > T

5

Conserved

Active site

(Toro et al. 2003)

MCUL

14

Asn188

Ser

N188S

c.563A > G

5

Conserved

Active site

(Toro et al. 2003)

MCUL

15

Pro192

Leu

P192L

c.575A > G

5

Conserved

In core helice

(Chuang et al. 2005)

MCUL

16

Met195

Thr

M195T

c.584 T > C

5

Conserved

In core helice

(Toro et al. 2003)

MCUL

17

His196

Arg

H196R

c.587A > G

5

Conserved

In core helice

(Kiuru et al. 2002), (Lehtonen et al. 2004)

RCC, ULMS

18

Ile229

Thr

I229T

c.686 T > C

5

Not conserved

Surface

(Alam et al. 2005b)

MCUL

19

Lys230

Arg

K230R

c.689A > G

5

Conserved

Subunit stabilization

(Tomlinson et al. 2002), (Coughlin et al. 1998), (Manning et al. 2000)

FHD

20

Arg233

Cys

R233C

c.697 C > T

5

Conserved

Active site

(Rustin et al. 1997), (Chuang et al. 2005), (Wei et al. 2006)

FHD, HLRCC, MCUL

21

Arg233

His

R233H

c.698 G > A

5

Conserved

Active site

(Tomlinson et al. 2002), (Alam et al. 2005b), (Wei et al. 2006), (Chuang et al. 2005), (Toro et al. 2003)

HLRCC, MCUL

22

Arg233

Leu

R233L

c.698 G > T

5

Conserved

Active site

(Chuang et al. 2005), (Toro et al. 2003)

MCUL

23

Ala239

Thr

A239T

c.715 G > A

5

Conserved

Near active site

(Lehtonen et al. 2004)

UL

24

Ala274

Thr

A274T

c.820 G > A

6

Not conserved

Active site

(Ylisaukko-oja et al. 2006)

OMC

25

Gly282

Val

G282V

c.845 G > T

6

Conserved

Active site

(Tomlinson et al. 2002), (Alam et al. 2005b)

MCUL

26

Ala308

Thr

A308T

c.922 G > A

7

Conserved

Surface

(Coughlin et al. 1998)

FHD

27

Asn310

Tyr

N310Y

c.928A > T

7

Conserved

Surface

(Alam et al. 2005b)

MCUL

28

Phe312

Cys

F312C

c.935 T > G

7

Conserved

Surface

(Coughlin et al. 1998)

FHD

29

His318

Tyr

H318Y

c.952 C > T

7

Semi-conserved

In core helice

(Toro et al. 2003), (Martinez-Mir et al. 2003)

HLRCC

30

His318

Leu

H318L

c.953A > T

7

Semi-conserved

In core helice

(Deschauer et al. 2006)

FHD

31

Val322

Asp

V322D

c.964 T > A

7

Conserved

In core helice (interaction with 1 other monomer)

(Toro et al. 2003)

MCUL

32

Thr330

Pro

T330P

c.988A > C

7

Semi-conserved

In core helice (interaction with 1 other monomer)

(Chuang et al. 2005)

MCUL

33

Cys333

Tyr

C333Y

c.998 G > A

7

Semi-conserved

In core helice (interaction with 1 other monomer)

 

MCUL

34

Ser334

Arg

S334R

c.1002 T > G

7

Conserved

In core helice (interaction with 1 other monomer)

(Badeloe et al. 2006)

CL

35

Leu335

Pro

L335P

c.1004 T > C

7

Conserved

In core helice

(Toro et al. 2003)

MCUL

36

Asn340

Lys

N340K

c.1020 T > A

7

Semi-conserved

In core helice

(Toro et al. 2003), (Wei et al. 2006)

MCUL

37

Glu355

Lys

E355K

c.1063 G > A

7

Conserved

Subunit stabilization

(Alam et al. 2005b)

MCUL

38

Asn361

Lys

N361K

c.1083 T > A

7

Conserved

Active site

(Alam et al. 2005b)

HLRCC-CDC

39

Glu362

Gln

E362Q

c.1084 G > C

7

Conserved

Active site

(Bourgeron et al. 1994)

FHD

40

Ser365

Gly

S365G

c.1093 G > A

7

Conserved

Active site

(Toro et al. 2003), (Wei et al. 2006)

MCUL

41

Ser366

Asn

S366N

c.1097 G > A

7

Conserved

Active site (but out)

(Toro et al. 2003), (Alam et al. 2005b)

MCUL

42

Met368

Thr

M368T

c.1103 T > C

7

Conserved

Active site

(Badeloe et al. 2006)

MCUL

43

Pro369

Ser

P369S

c.1105 C > T

7

Conserved

Active site (but out)

(Maradin et al. 2006)

FHD

44

Asn373

Ser

N373S

c.1118A > G

8

Conserved

Active site

(Lehtonen et al. 2004)

HLRCC/clear cell RCC

45

Gln376

Pro

Q376P

c.1127A > C

8

Conserved

In core helice (interaction with 1 other monomer)

(Zeman et al. 2000), (Remes et al. 2004), (Phillips et al. 2006)

FHD

46

Ala385

Asp

A385D

c.1154 C > A

8

Not conserved

In core helice (interaction with 2 other monomers)

(Wei et al. 2006)

MCUL

47

Val394

Leu

V394L

c.1180 G > C

8

Not conserved

In core helice

(Martinez-Mir et al. 2003)

MCUL

48

Gly397

Arg

G397R

c.1189 G > A

8

Semi- conserved

In core helice

(Alam et al. 2005b)

MCUL

49

His402

Cys

H402C

c.1207 C > T

8

Conserved

In core helice turn (interaction with 2 other monomers)

(Phillips et al. 2006)

FHD

50

Ser419

Pro

S419P

c.1255 T > C

9

Conserved

In core helice

(Wei et al. 2006)

HLRCC

51

Asp425

Val

D425V

c.1274A > T

9

Conserved

In core helice (interaction with 1 other monomer)

(Coughlin et al. 1998)

FHD

52

Gln439

Pro

Q439P

c.1316A > C

9

Not conserved

Surface

(Wei et al. 2006)

HLRCC

53

Met454

Ile

M454I

c.1362 G > A

9

Conserved

Subunit interaction

(Carvajal-Carmona et al. 2006)

LCT

54

Tyr465

Cys

Y465C

c.1394A > G

10

Semi- conserved

Surface

(Toro et al. 2003)

MCUL

55

Leu507

Pro

L507P

c.1520 T > C

10

Semi- conserved

Surface near opening active site

(Alam et al. 2005b)

MCUL

Fig. 2

Clustering of human fumarase missense mutations observed in FHD, MCUL1 and HLRCC. The active site is highlighted in cyan. Positions of amino acid mutations are indicated as small spheres and numbered according to Table 2. The positions around the active site are indicated in red, mutations affecting inter- or intrasubunit interactions are indicated in dark yellow. For clarity, one monomeric subunit is omitted

Notes

Acknowledgments

Help in data collection at SLS (Swiss Light Source, Villigen, CH) by Frank von Delft, Annette Roos and Panagis Filippakopoulos is gratefully acknowledged. The Structural Genomics Consortium is a registered charity (Number 1097737) funded by the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomic institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Innovation, Merck and Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust. The study was supported by the NIHR Oxford Biomedical Research Unit.

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Copyright information

© The Author(s) 2011

Authors and Affiliations

  • Sarah Picaud
    • 1
  • Kathryn L. Kavanagh
    • 1
  • Wyatt W. Yue
    • 1
  • Wen Hwa Lee
    • 1
  • Susanne Muller-Knapp
    • 1
  • Opher Gileadi
    • 1
  • James Sacchettini
    • 2
  • Udo Oppermann
    • 1
    • 3
  1. 1.Structural Genomics ConsortiumUniversity of OxfordHeadingtonUK
  2. 2.Department of Biochemistry & BiophysicsTexas A&M UniversityCollege StationUSA
  3. 3.Botnar Research CenterNIHR Oxford Biomedical Research UnitOxfordUK

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