Chemistry (including Biochemistry)/Molecule comparison


QUESTION: If a person has previously reacted badly to penicillamine, how likely would it be for that person to have a similar reaction to n- acetylcysteine aka NAC. I understand that the side effects associated with penicillamine are caused by an intolerance to thiols. If this is the case, wouldn't n-acetylcysteine also be dangerous? I ask because a person who has an autoimmune condition has been told to take NAC for their lung fibrosis. I am concerned that the supplement could have similar effects as penicillamine. I was told by the person's doctor that they are totally different drugs and work in different ways. But penicillamine is a cysteine analog and NAC is a cysteine metabolite. Both contain a sulphydryl. Poor sulfoxidation is said to be the cause behind the side-effects of penicillamine. I am hoping for some clarification with regards to how these molecules differ in terms of metabolism if they would not have a similar side-effect profile. I need to put my mind at ease. Thank you very much! :)

ANSWER: Hi Charles!

If you look at the two structures,


You'll notice that both have sulfhydryls, yes. However, on NAC we have two keto groups. (C=O double bonds). My best guess is that the second keto group on NAC will decrease the likliehood of NAC losing its sulfhydryl hydrogen for long, as temporary bonds with C-O-H could pass the H right back. Put another way, C=O bonds have regions of negative charge around them. S-H is slightly positive, and S- negative. There are more instances of the S-H finding another H rather than finding another S to bond to. It comes with its own condom, so to speak.

My trip through Google Scholar seems to indicate that it is the high likliehood of penicillamine to make S-S double bonds that causes side effects. Since NAC has steric hindrance (a shield) to making S-S double bonds, the incidence of bad side effects should be lower.

I hope your friend feels better soon!

---------- FOLLOW-UP ----------

QUESTION: Thank you, Trista!

So the negative side effects are caused by a loss of sulphur or sulphur bridges on the patient's part?

I'm still a little confused about one thing. From what I've read about NAC, it is used as a mucolytic. I understand that it is because of its ability to break up disulphide bonds that it works this way. I assumed by this that it was able to exchange h for s. I'm still a bit confused, but I'm getting closer to understanding! I also read that the problem was caused by an inability to oxidize sulfur. Is this related to sulphur bridges? I read the sulfur oxidation thing here;

Thank you so much for your time!

Hi! Sorry this is late; I'm teaching and I caught a cold.

To oxidize sulphur is to take away its electrons. When NAC (-SH) is used to oxidize sulphur, it converts some of the S-S bonds holding mucins (mucus proteins) together into -S-S-NAC bonds, giving one of the mucin -S's the other electron pair. This breaks up the conglomeration of mucins, and the mucin-S-S-NAC can be expelled.

I suspect that the negative side effects of penicillamine is that the S on penicillamine is much more free to make disulfide bonds with any other S it encounters, rather than more precisely fitting into mucin proteins.

A 'poor sulfoxidizer' has trouble converting two X-S-H molecules into X-S-S-X + 2e- and 2H+. If you have many X-S-H bonds in your system, and you give your system a large amount of something that will cross them up, this may be the source of side effects.

Make sense?

Thanks for your patience.

Chemistry (including Biochemistry)

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Trista Robichaud, PhD


No homework questions, especially ones copied and pasted from textbooks. I will answer questions about principles or give hints, but I do not do other's homework. I'm comfortable answering basic biochemistry, chemistry, and biology questions up to and including an undergraduate level of understanding. This includes molecular biology, protein purification, and genetics. My training/inclination is primarily in structural biology, or how the shapes of things affect their function. Other interests include protein design, protein engineering, enzyme kinetics, and metabolic diseases such as cancer, atherosclerosis, and diabetes. My chemistry weaknesses are that I do not know organic or inorganic synthesis well, nor am I familiar with advanced inorganic reactions. I will attempt quantum mechanics and thermodynamics questions, but primarily as they relate to biological systems. Furthermore, I cannot tell you if a skin photograph is cancerous, or otherwise diagnose any disease. I can tell you how we currently understand the basic science behind a disease state, but I cannot recommend treatment in any way. Please direct such questions to your medical professional.


I hold a PhD in Biomedical Science from the University of Massachusetts Medical School in Worcester. I specialize in Biochemistry, with a focus on protein chemistry. My thesis work involved the structure and functions of the human glucose transporter 1. (hGLUT1) Currently I am a postdoc working in peptide (mini-protein) design and enzymology at the University of Texas Health Science Center in San Antonio, Texas. I am in Bjorn Steffensen's lab (PhD, DDS), studying gelatinase A and oral carcinoma.

2001 American Association for the Advancement of Science
2007 American Chemical Society
2007 Protein Society
2011 UTHSCSA Women’s Faculty Association

Levine KB, Robichaud TK, Hamill S, Sultzman LA, Carruthers A. Properties of the human erythrocyte glucose transport protein are determined by cellular context. Biochemistry 44(15):5606-16, 2005. (PMID 15823019)
Robichaud TK, Appleyard AN, Herbert RB, Henderson PJ, Carruthers A “Determinants of ligand binding affinity and cooperativity at the GLUT1 endofacial site” Biochemistry 50(15):3137-48, 2011. (PMID 21384913)
Xu X, Mikhailova M, Chen Z, Pal S, Robichaud TK, Lafer EM, Baber S, Steffensen B. “Peptide from the C-terminal domain of tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) inhibits membrane activation of matrix metalloproteinase-2 (MMP-2)” Matrix Biol. 2011 Sep;30(7-8):404-12. (PMID: 21839835)
Robichaud TK, Steffensen B, Fields GB. Exosite interactions impact matrix metalloproteinase collagen specificities. J Biol Chem. 2011 Oct 28;286(43):37535-42 (PMID: 21896477)

Poster Abstracts:
Robichaud TK, Carruthers. A "Mutagenesis of the Human type 1 glucose transporter exit site: A functional study." ACS 234th Meeting, Boston MA. Division of Biological Chemistry, 2007
Robichaud TK, Bhowmick M, Tokmina-Roszyk D, Fields GB “Synthesis and Analysis of MT1-MMP Peptide Inhibitors” Biological Chemistry Division of the Protein Society Meeting, San Diego CA 2010
Robichaud TK; Tokmina-Roszyk D; Steffensen B and Fields GB “Catalytic Domain Exosites Contribute to Determining Matrix Metalloproteinase Triple Helical Collagen Specificities” Dental Science Symposium. UTHSCSA 2011
Robichaud TK; Tokmina-Roszyk D; Steffensen B and Fields GB “Exosite Interactions Determine Matrix Metalloproteinase Specificities” Gordon Research Conference on Matrix Metalloproteinase Biology, Bristol RI 2011

Oakland University, Auburn Hills MI BS, Biochemistry 1998
University of Massachusetts Medical School, Worcester MA PhD, Biochemistry & Molecular Pharmacology 2001-2008
University of Texas Health Science Center, San Antonio TX Postdoc, Biochemistry 2009-Present

Awards and Honors
1998 Honors College Graduate, Oakland University
2009 Institutional National Research Service Award, Pathobiology of Occlusive Vascular Disease T32 HL07446
2011 1st Place, Best Postdoctoral Poster, Dental Science Symposium, UTHSCSA, April 2011

Past/Present Clients
Invited Seminars:
Robichaud TK, Fields GB. “Synthesis and Analysis of MTI-MMP Triple Helical Peptide Inhibitors” Pathology Research Conference, University of Texas Health Science Center San Antonio Pathology Department (June 18th, 2010)
Robichaud TK & Hill, B “How To Give A Great Scientific Talk” Invited Lecture, Pathobiology of Occlusive Vascular Disease Seminars, UTHSCSA (Nov 11th 2010), Cardiology Seminar Series, Texas Research Park (Feb 21st, 2011)
Robichaud TK; Tokmina-Roszyk D; Steffensen B and Fields GB “Exosite Interactions Determine Matrix Metalloproteinase Specificities” Gordon-Keenan Research Seminar “Everything You Wanted to Know About Matrix Metalloproteinases But Were Afraid to Ask” Bristol, RI (Aug 6th, 2011)

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