angiotensin i-converting enzyme (ace): from bench to clinic angiotensin i-converting enzyme (ace):...
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Angiotensin I-Converting Enzyme (ACE):
From Bench To Clinic
Angiotensin I-Converting Enzyme (ACE):
From Bench To Clinic
ByByDr. Amr S. MoustafaAss. Prof. and Consultant
Medical Biochemistry Dept.
Dr. Amr S. MoustafaAss. Prof. and Consultant
Medical Biochemistry Dept.
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OutlinesOutlinesACE ProteinACE GeneACE PolymorphismACE and DiseasesSummary and ConclusionsACE Inhibitors
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OutlinesOutlinesACE ProteinACE GeneACE PolymorphismACE and Diseases
Summary and ConclusionsACE Inhibitors
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ACE ProteinACE ProteinStructure: Zinc-Metallopeptidase (EC 3.4.15.1)
Physiological Functions
Substrates: Natural and SyntheticDistribution
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ACE Isoforms
ACE Isoforms
*Somatic Testicular
Gene 17q23 17q23
Distribution Endothelial and
Epithelial
Sperm
Mr in kDa 146 (160) 80 (90)
Active site(s) 2 plus 2 Zn 1 plus 1 Zn
*ACE2 : Regulator of cardiac function
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Structure of sACE and gACE
Structure of sACE and gACE
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The 3-D Structure of gACE
The 3-D Structure of gACE
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ACE ProteinACE ProteinStructure: Zinc-Metallopeptidase
Physiological Functions
Substrates: Natural and Synthetic
Distribution
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ACE SubstratesACE Substrates
Natural: Angiotensin I Bradykinin Others, neuropeptides, hematopoietic, …
Synthetic: Hippuryl-glycyl-glycine Hippuryl-histidyl-leucine (HHL) Furylacryloyl-phenylalanyl-glycyl-glycine (FAPGG)
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ACE DistributionACE Distribution
Cellular Origin: Vascular Endothelium Others: Epithelial, Neuronal, …
Tissue Distribution: Lungs, Brain, kidneys, adrenals Male Reproductive tract
Plasma ACE
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Physiological Functions
Physiological Functions
Vascular toneCardiac Functions
Neuronal Metabolism
Reproduction
Hematopoiesis
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Renin-Angiotensin System
Renin-Angiotensin System
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Measurement of ACE
Measurement of ACE
ACE Activity: Spectrophotometric, Flurometric, Radiometric, Chromatographic
Synthetic substrates
ACE Level: ELISA and Radioimmunoassay
Specific anti-human ACE antibody
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Plasma ACE Level
Plasma ACE Level
ACEGranulomatous:
Sarcoidosis, SilicosisGaucher, Leprosy
Non-granulomatous:Hyperthyroidism, Cholestasis
ACEVascular endothelial damage
DVTChemo-toxicity in cancer treatment
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Plasma ACE LevelPlasma ACE Level
Large inter-individual variation:
Ref. range 37-202 ng/ml ~ Six fold
Sex, Age, Hormonal, Environmental, . .
Gene Effect:
Similar intra-familial ACE levels
And/or
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ACE GeneACE Gene
Structure
Polymorphism
Genotype/phenotype
Polymorphism and diseases
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Structure of ACE GeneStructure of ACE Gene
3’ 5’
E1 E13 E14 E26
DNA
E1 E12 E14 E26
5’ 3’mRNA
E13E14 E26
5’ 3’mRNA
sACE
gACE
ACE
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ACE Gene Insertion/Deletion (I/D)
Polymorphism
ACE Gene Insertion/Deletion (I/D)
Polymorphism
Two alleles: I and DThree Genotypes: II, ID, and DD
I or D of 287 bp in intron 16
Clinical Significance: Linkage to diseases: Controversial Intron location: No direct effect on ACE expression
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PCR for ACE genotypesPCR for ACE genotypes
1 2 3 4
490 bp
190 bp
II ID DD
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The Relationship Between
Genotype/Phenotype of ACE
The Relationship Between
Genotype/Phenotype of ACE
GenotypeII
(N = 14)
ID
(N = 37)
DD
(N = 29)
Distribution 18% 46% 36%
Phenotype
ACE ng/ml299+49 393+67 494+88
Allele Frequency: I = 0.4 and D = 0.6
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Genotype/Phenotype of ACE
Caucasian Vs Asian
Genotype/Phenotype of ACE
Caucasian Vs Asian
Caucasian Asian
DD Genotype 36% 14%
ACE level60% higher DD than II
No differenceDD and II
Best response to ACEi
DD II
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ACE I/D Polymorphism and Diseases: Heart
Diseases
ACE I/D Polymorphism and Diseases: Heart
Diseases
DD and ID are independent risk factors for CAD in Turkish
DD and ID are associated with CHD
DD is associated with heart failure progression and worsens its outcome
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ACE I/D Polymorphism and Diseases: T2DM
ACE I/D Polymorphism and Diseases: T2DM
DD is associated with T2DM and its renal and vascular complications in Caucasian
DD is a risk factor DM and Nephropathy in Japanese
DD is a risk factor for renal Complications in Chinese
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ACE I/D Polymorphism and Diseases: Nephropathy
ACE I/D Polymorphism and Diseases: Nephropathy
DD showed higher frequency in non-SS INS in Taiwan
II is more frequent in SS-nephrotic Syndrome in India
No difference in genotype frequencyin NS in Indonesia
No difference in genotype frequencyin DM with ESRD in Taiwan
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ACE InhibitorsACE Inhibitors
The first was Captopril, 1981
Design and mechanism: The active site for carboxpeptidase A Tight-binding to the active site Thiol or other groups coordinate Zn
Mixed-type inhibition: Plasma and membrane-bound ACE
Little discrimination for the 2 active sites
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ACE Inhibitors: Clinical Uses
ACE Inhibitors: Clinical Uses
First-line therapy: Hypertension Congestive heart failure Myocardial infarction
Other common indications: Nephropathy Renal transplant patients
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ACE Inhibitors: Limitations
ACE Inhibitors: Limitations
Varied response among different persons
? Modulating effect of ACE I/D polymorphism Better response in DD Vs II Caucasian
Pharmacogenetic Tests: Would screening for I/D polymorphism before prescription of ACE inhibitors be cost-effective? (Pharmacoeconomic)
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ACE Inhibitors: Future
ACE Inhibitors: Future
New generation of ACE inhibitors: Recent crystal-structure Less side effects More clinical effectiveness
Active-site specific inhibitors: N- or C-
ACE2-specific inhibitors
Tailor-made Therapy
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Conclusions-1Conclusions-1Molecular cloning and crystal-structureof ACE: Rapid advance and More focus on ACE research
ACE I/D polymorphism and diseases:
Debate and Paradox Better research design Careful reporting of genetic data
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Conclusions-2Conclusions-2
Genetic-based therapy is not yet a common clinical practice; but, genetic targeting will become the standard medical care soon
Development of new generation of ACE inhibitors is warranted
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Conclusions-3Conclusions-3$Sutton’s Low of Clinical Research:
The research energies should be directed where the clinical impact is likely highest; i.e., “to go where the money is”
$Willie Sutton (1950):
A famous Chicago bank robber
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AcknowledgmentAcknowledgment
Prof. Bruno Baudin, Saint-Antoine Hospital Paris, France and
Universite de Basse Normandie, France