MAO A and MAO B

1
MAO A and MAO B

• PDP ID 1GOS
• By Serge Farinas, Lauren Ogilvie, Kadiatu
  Jalloh, and Xuan Duong

2
What are MAOS?

• Monoamine oxidase
• .enzymes
• .oxidize monoamines
• .neurotransmitters
• Types MAO A and MAO B
• A liver, GI tracts and placenta
• B mitochondrial outer membranes of cells,
  and
• blood platelets.
• both found in neurons

3
General Information

• Belongs to flavin protein family
• .cofactor FAD
• found in mammals ex. humans and mice

4
Types

• Varies based on substrate
• MAO A oxidizes serotonin and
• norepinephrine
• MAO B oxidize phenyl-ethylamine
• Both oxidized dopamine, epinephrine and
• tyramine

5
(No Transcript)
6
(No Transcript)
7
Mechanism
8
(No Transcript)
9
Disorders

• Depression
• Attention deficit disorders
• Substance abuse
• Various neurological disorders

10
Human Monoamine Oxidase

• Structure
• 8020 atoms
• 2 AA Chains
• 2 central ligands

A
497

• Chains A B
• almost identical
• difference of a
• few bases (may
• be missing)

B
493
11
Secondary Structure

• Chains A B equivalent
• 13 Alpha Helices
• 19 Beta Strands

12
Ligands

• 2 Ligands
• Flavin-Adenine Dinucleotide (FAD)
• N-(E)-Methyl(Phenyl)-N-
• (E)-2- Propenylidene
• Methanaminium (NYP)

NYP
FAD
13
Ligands

• FAD
• Reaction center
• Isoalloxazine ring system
• Redox reactions
• oxidized form
• attached nucleotide

FAD
14
Ligands
NYP

• Role not known
• Stabilization for X-Ray?

15
AA/Ligand Interactions

• Residues
• Cysteine (nucleophile, covalent bonding)
• Tyrosine (H stabilizing)
• Glutamic acid (charge stabilization)

16
Classification

• Oxioreductase
• catalyzes reduction and oxidation (redox)
  reactions
• FAD (oxidized)
• FADH (partially reduced)
• FADH2 (fully reduced)

17
Structure

• Structural Motifs
• 145-149, (1) N Glycolysation site
• 2-221, (7) Protein kinase C phosphorylation site
• 111-484, (8) Casein kinase II phosphorylation
  site
• 386-423, (2) Tyrosine kinase phosphorylation
  site
• 11-444, (8) N-myristoylation site

18
Structure

• Protein Prediction vs. Crystal Structure
• Alpha Helices
• Predicted 11
• X-Ray 13
• Beta Strands
• Predicted 16
• X-Ray 19

19
Structure

• Transmembrane helix
• Predicted at 490

20
Related Structures

• Mutants
• Many found
• Examples
• 1. Monoamine oxidase B mutant (PDB 2C76)
• functional study- aromatic cage
• 2. Monoamine oxidase B I199f (PDB 2BK5)
• importance of specific AA base

21
Computational Tools

• Protein Explorer and PDB Viewer
• Cn3D
• Entrez
• Algorithms
• PROSEARCH
• BLASTP
• TMHMM
• TMAP
• PELE
• GOR4

22
Multiple Sequence Alignment
23
Trees
? 88.8
99.9 ?
24
Distance Matrices

• (1) (2)
  (3) (4) (5)
• (1) Orangutan 0.00000 0.00863 0.13277
  0.60490 0.77390
• (2) Human 0.00863 0.00000
  0.13001 0.59930 0.77698
• (3) Horse 0.13277 0.13001
  0.00000 0.56740 0.78040
• (4) Platypus 0.60490 0.59930
  0.56740 0.00000 1.25236
• (5) Chimpanzee 0.77390 0.77698 0.78040
  1.25236 0.00000
• (1)
  (2) (3) (4) (5)
• Orangutan (1) 0.000 0.004 0.065 0.200
  0.264
• Human (2) 0.004 0.000 0.063
  0.198 0.264
• Horse (3) 0.065 0.063 0.000
  0.196 0.264
• Platypus (4) 0.200 0.198 0.196
  0.000 0.351
• Chimp (5) 0.264 0.264 0.264
  0.351 0.000

25
Interesting Facts . . .

• Disorders resulting from MAO dysfunction
• Unusually high or low levels of MAOs
• Depression
• Monoamine oxidase inhibitors- treatment of
  depression
• Risky due to drug interaction with diet and drugs
• Substance abuse
• Attention deficit disorder
• Irregular sexual maturation

26
Interesting Facts . . .

• Disorders resulting from MAO dysfunction
• Brunner syndrome
• Rare mutations
• MAO A gene deficiency excess of catecholamines
  in bloodstream (seratonin, dopamine, and
  epinephrine)
• Mental retardation
• Impulsive behavior (arson, attempted raping,
  agressiveness)

27
Interesting Facts . . .

• Disorders resulting from MAO dysfunction
• Parkinsons Disease
• High levels of MAO B
• Slowness of movement
• Impaired balance and coordination
• Tremors (shakings in hands, arms, legs, jaw)
• MAO B inhibitors- causes dopamine to accumulate
  in surviving nerve cells, reduces PD symptoms
• Brains of smokers have 40 decrease in MAO B

28
Interesting Facts

• Disorders resulting from MAO dysfunction
• Alzheimer's Disease
• High levels of MAO B
• Affects thought, memory and language
• MAO B inhibitor used to treat AD

29
References Cited

• Benedetti SM,Bona L, Gallina M, Persiani S,
  Sanson G, Tipton KF. 1998. Oxidation of
  dopamine by the two forms of monoamines. Neural
  Transm Suppl. 1998 52233-8.
• Binda C, Collibus D, Edmonson DE, Lustig A, Li M,
  Matteviproc A. 2005. Three-dimensional structure
  of human monoamine oxidase A (MAO A) Relation to
  the structures of rat MAO A and human MAO. Natl
  Acad Sci U S A. 1021268412689
• Fowler, J.S., Volkow, N.D., et al. (1996).
  Inhibition of monoamine oxidase B in the brains
  of smokers. Nature. 379733-736.
• Patric GL. 2005. An introduction to Medicinal
  chemistry. 3rd. Ed. Pg(595-614)

30
References Cited

• Shih, J., Thompson, R. (1999). Monoamine oxidase
  in neuropsychiatry and behavior. The American
  Journal of Human Genetics. 65(2)593-598.
• Thomas, T. (2000). Monoamine oxidase-B inhibitors
  in the treatment of Alzheimer's disease.
  Neurobiology of Aging. 21343-348.
• Yong, V.W., Perry, T.L. (1986). Monoamine oxidase
  B, smoking, and Parkinsons disease. Journal of
  the Neurological Sciences. 72(2-3)265-272.