Tazobactam/تازوباکتام

Tazobactam/

تازوباکتام

Tazobactam
Systematic (IUPAC) name


(2S,3S,5R)-3-Methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	B
Routes of administration	Intravenous
Legal status
Legal status	℞ (Prescription only)
Identifiers
CAS Number	89786-04-9
ATC code	J01CG02 (WHO)
PubChem	CID 123630
DrugBank	DB01606
ChemSpider	110216
UNII	SE10G96M8W
KEGG	D00660
ChEBI	CHEBI:9421
ChEMBL	CHEMBL404
Chemical data
Formula	C₁₀H₁₂N₄O₅S
Molar mass	300.289 g/mol


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Tazobactam is a pharmaceutical drug that inhibits the action of bacterial β-lactamases, especially those belonging to the SHV-1 and TEM groups. It is commonly used as its sodium salt, tazobactam sodium.
Tazobactam is combined with the extended spectrum β-lactam antibiotic piperacillin in the drug piperacillin/tazobactam, used in infections due Pseudomonas aeruginosa. Tazobactam broadens the spectrum of piperacillin by making it effective against organisms that express β-lactamase and would normally degrade piperacillin.
Tazobactam is a heavily modified penicillin and a sulfone.

سیدنی برنر/Sydney Brenner

سیدنی برنر (Sydney Brenner) (زاده ۱۳ ژانویه ۱۹۲۷) زیست‌شناس اهل آفریقای جنوبی است. وی در سال ۲۰۰۲ به‌همراه رابرت هرویتس و جان سالستن برنده جایزه نوبل فیزیولوژی و پزشکی شد. برنر سهم قابل توجهی در کار روی رمز ژنتیکی و دیگر زمینه‌های زیست‌شناسی مولکولی در حین کار در واحد شورای پژوهش‌های پزشکی در کمبریج، انگلستان، داشت.

http://www.dnarna.org/en/images/stories/nobl/148.jpg

نوبل پزشکي براي ژن هاي مرگ

جایزه نوبل پزشکی امسال به «سیدنی برنر» و «سر جان سالستون» از بریتانیا و «رابرت هورویتز» از امریکا اهدا می شود. این 3 نفر به خاطر مطالعات خود در زمینه چگونگی کنترل تقسیم سلولها و شکل گیری اعضای بدن به وسیله ژنها، مستحق دریافت جایزه تشخیص داده شده اند.

موسسه نوبل در تقدیرنامه خود برای این 3 دانشمند نوشته که مطالعات آنها به درک نحوه شکل گیری و گسترش بسیاری از بیماری ها کمک کرده است . یکی از کشفیات این دانشمندان ، درک سازوکار ژنتیکی کنترل مرگ برنامه ریزی شده سلولها در پایان دوره زیستی آنهاست .
آنها مطالعات خود را روی کرمهای آغازی نماتود (Nematode) انجام داده اند که کمتر از یک میلی متر طول دارند و این مطالعات به آنها کمک کرده است فرآیند بیماری های مختلف در انسان ،ازجمله بیماری سرطان را کشف کنند که طی آن مرگ برنامه ریزی شده سلولها بموقع روی نمی دهد و همچنین بیماری هایی مثل ایدز، سکته مغزی و قلبی که در آن سلولها به دلیل مرگ ومیر بیش از حد نابود می شوند.خبر اعطای جایزه نوبل پزشکی به این 3 زیست شناس که ارزش آن 10 میلیون کرون سوئد (بالغ بر یک میلیون دلار) است ، روز دوشنبه هفتم اکتبر در استکهلم اعلام شد.
سیدنی برنر، 75 ساله که در موسسه علوم ملکولی در شهر برکلی کالیفرنیا کار می کند، باپروفسور «فرنسیس کریک»، یکی از کاشفان ساختمان DNAهمکاری نزدیک داشته است .او همچنین کاشف «آر.ان .ای» است که اطلاعات ژنتیکی را از DNA به سلول منتقل می کند.به گفته هیات داوران نوبل ، او با کشف ارتباط میان جهش های خاص ژنتیکی و تاثیر آنها بر رشد اعضای بدن ، مرزهای دانش را در هم شکسته است .
جان سالستون 60 ساله ، بنیانگذار موسسه «سنگر» در کمبریج است که در سال 1992 توسط موسسه های «ولکام تراست» و «شورای تحقیقات پزشکی »بریتانیا برای پژوهش در زمینه ژنتیک انسانی تاسیس شد.این موسسه همچنین بشدت درگیر شمارش «DNA» انسان در «پروژه ژنوم انسانی» بوده است.
رابرت هورویتز 55 ساله که در موسسه فنی ماساچوست (ام .آی .تی ) امریکا کار می کند، نخستین «ژنهای مرگ» را کشف کرده که دو ژن در کرمهای بدوی هستند و نشان داده که انسان نیز دارای ژنی مشابه یکی از آنهاست.
به دنبال تحقیقات رابرت هورویتز بوده که اکنون مشخص شده است در بدن انسان نیز ژنهایی وجود دارد که مشابه اکثر ژنهایی هستند که در کرمها مرگ سلولی را کنترل می کنند.
بنابر بیانیه هیات داوران موسسه نوبل ، تحقیقات این دانشمندان درک عمیق تری از نحوه تقسیم سلولی ، شکل گیری بافتها و مرگ آنها پس از انجام وظیفه ، فراهم کرده است .جایزه نوبل پزشکی روز دهم دسامبر طی مراسمی به برندگان اعطاء خواهد شد.

دومین نوبل امسال برای ژاپنی ها

جایزه نوبل سال 2002 در رشته شیمی در تقدیر از پژوهش هایی اعطا می شود که دانش بشررا در زمینه مولکول های بزرگ و پیچیده مانند پروتئین ها که بدن انسان از آن تشکیل شده و به وسیله آن نگهداری می شود، افزایش داده است .

این جایزه 10 میلیون کرونی (یک میلیون دلاری ) را «جان فن» از امریکا، «کویچی تاناکا» از ژاپن و «کورت ووتریخ» از سوئیس میان خود تقسیم خواهند کرد.

این 3 نفر شالوده دانش جدید «پروتئومیکس» را ریخته اند که به چگونگی کنش و واکنش پروتئین ها با سایر مواد تشکیل دهنده سلول ها و نقش آنها در حیات بشر می پردازد. دانش پروتئومیکس با کمک داده هایی که «پروژه ژنوم انسانی» فراهم کرده ، نسل تازه داروهایی را پدید می آورد که بسیار موثرتر از داروهای فعلی اند و حتی می تواند برای هر بیمار داروی خاص او را ساخت.

شیوه جدید

موسسه نوبل در تقدیرنامه خود برای دریافت کنندگان نوبل شیمی امسال نوشته است که آنهابرای مطالعه ملکول های زیستی بزرگ مانند پروتئین ها، شیوه های تحلیلی کارآمدی فراهم آورده اند.در این تقدیرنامه آمده است : امکان تجزیه و تحلیل جزیی پروتئین ها به افزایش درک ما ازفرآیندهای حیاتی افزوده است .

تحقیقات این 3 نفر به دانشمندان کمک کرده است درک بهتری از چگونگی کارکرد سلول ها دربدن حاصل کنند و شیوه تازه ای برای شناسایی بیماری ها در اختیارشان گذاشته است .به گفته «بنگت نوردن» رئیس کمیته نوبل در رشته شیمی ، برندگان نوبل امسال با یافته های خود راه را برای کشفیات آتی در زمینه درمان سرطان هموار کرده اند و بدون این یافته ها،داروسازی نوین به وجود نمی آمد.

فن و تاناکا در دهه 1980 نشان دادند چگونه می توان تکنیکی به نام «طیف سنجی انبوه» را که برای تعیین عناصر حاضر در نمونه آزمایشگاهی به کار می رود، برای شناسایی پروتئین ها به کار گرفت .

در گذشته ، طیف سنجی انبوه تنها قادر به شناسایی ملکول های ریز بود. کورت ووتریخ نیز در دهه 1980 روش شناسایی شیمیایی دیگری به نام «ان ام آر» ابداع کرد وامکان استفاده از این روش را روی پروتئین ها و بویژه مطالعه محیطهای مشابه محیط سلول های زنده فراهم آورد.

فن و تاناکا نیمی از جایزه نوبل را میان خود تقسیم می کنند و نیم دیگر به ووتریخ تعلق می گیرد.جان فن که در دانشگاه مشترک المنافع ویرجینیای امریکا در شهر ریچموند کار می کند، اکنون 85 سال دارد.

کوچی تاناکای 43 ساله برای شرکت «شیمادزو» در شهر کیوتوی ژاپن کار می کند.کورت ووتریخ 64 ساله با موسسه فنی فدرال سوئیس در زوریخ و موسسه «تحقیقاتی اسکریپس» در کالیفرنیا همکاری می کند.

تاناکا، جوان ترین برنده جایزه نوبل رشته شیمی از سال 1934 تاکنون و دومین برنده جایزه نوبل در سال جاری از ژاپن است . ماساتوشی کوشیبا از ژاپن برای دریافت جایزه نوبل فیزیک انتخاب شده بود

کورت ووتریش /Kurt Wüthrich

کورت ووتریش (به آلمانی: Kurt Wüthrich) (متولد ۴ اکتبر ۱۹۳۸) شیمی‌دان و زیست‌فیزیک‌دان سوئیسی و برنده جایزه نوبل شیمی است. در سال ۲۰۰۲ «برای توسعه روش برای شناسایی و تجزیه و تحلیل ساختار مولکول‌های بیولوژیکی و تعیین ساختار سه بعدی ماکرومولکولهای بیولوژیکی در محلول» موفق به دریافت جایزه نوبل شیمی شد.

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زندگی نامه

ووتریش در آربرگ، سوئیس زاده شد. در شیمی، فیزیک و ریاضیات از دانشگاه برن فارغ‌التحصیل شد و مدرک دکترا خود را از دانشگاه بازل در سال ۱۹۶۴ دریافت کرد. او مدتی در دانشگاه کالیفرنیا، برکلی مشغول به کار شد.

او در سال 1965 مدتی با دکتر رابرت کونیک مدیر پروژه ساخت بمب اتمی (مانهتان )کار کرد .

او از سال 1967 تا 1969 در ازمایشکاه تلفن بل مشغول بکار بود

او هم اکنون دارای یک ازمایشگاه در زوریخ و دیگری در موسسه تحقیقات اسکریپس در امریکا است

Karl Barry Sharpless/کارل بری شارپلس

کارل بری شارپلس ( Karl Barry Sharpless) (متولد ۲۸ آوریل ۱۹۴۱) شیمی‌دان آمریکایی و برنده جایزه نوبل است که در سال ۲۰۰۱ «برای کار دربارهٔ واکنش‌های اکسیداسون فعال شده توسط کاتالیزهای کایرال» به همراه ریوجی نویوری و ویلیام نولز موفق به دریافت جایزه نوبل در شیمی شد.

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زندگی‌نامه

شارپلس در فیلادلفیا، پنسیلوانیا به دنیا آمد. او در ۱۹۶۳ تحصیلات خود را در کالج دارتموث آغاز نمود و در سال ۱۹۶۸ دکترای خود را از دانشگاه استنفورد گرفت. پس از دریافت دکترای در دانشگاه استانفورد و دانشگاه هاروارد مشغول به کار شد او همچنین دارای مدرک افتخاری از دانشگاه فنی مونیخ است.

Research

Sharpless developed stereoselective oxidation reactions, and showed that the formation of an inhibitor with femtomolar potency can be catalyzed by the enzyme acetylcholinesterase, beginning with an azide and an alkyne. He discovered several chemical reactions which have transformed asymmetric synthesis from science fiction to the relatively routine, including aminohydroxylation, dihydroxylation, and the Sharpless asymmetric epoxidation.
In 2001 he won a half-share of the Nobel Prize in Chemistry for his work on chirally catalysed oxidation reactions (Sharpless epoxidation, Sharpless asymmetric dihydroxylation, Sharpless oxyamination). The other half of the year's Prize was shared between William S. Knowles and Ryōji Noyori (for their work on stereoselective hydrogenation).
He also successfully epoxidized (using racemic tartaric acid) a C-86 Buckminster Fullerene ball, employing p-Cresol as solvent. More recently he has been an important figure in the new field of click chemistry This involves a set of highly selective, exothermic reactions which occur under mild conditions; the most successful example is the azide alkyne Huisgen cycloaddition to form 1,2,3-triazoles.

The chemistry of ferrous bis-glycinate chelate

ALAN v.51 n.1 supl.1 Caracas mar. 2001

The chemistry of ferrous bis-glycinate chelate

Stephen D. Ashmead

Albion Laboratories, Inc., Clearfield, Utah U .S.A.

SUMMARY.

In order to produce a ferrous chelate tour criteria 1 must be met: 1) the ligand must contain two functional groups which are capable of entering into covalent and coordinate covalent bonds; 2) a ring structure with the ferrous ion being the closing member of the ring must be created; 3) the chelate must be ( sterically possible; and 4) the chelation reaction must be energetically possible. In addition to the above, a totally nutritionally functional ferrous chelate must meet three further criteria: 1) it must have low molecular weight; 2)its stability constant must be nutritionally functional; and 3) the ligand must be metabolizable by the body. When. ferrous iron is reacted with glycine and forms a bis-glycinate chelate, it meets all of the requirements of being both a chelate and being a totally nutritionally functional chelate.

Key words: Chelation, criteria for chelation, Ferrochel, amino acid chelates.

In 1893, Alfred Werner postulated a new molecular structure to describe those stable molecules. He had noted that certain structural entities, which he called "complexes", remained intact through a series of chemical transformations. As a result of those observations, he wrote, "If we think of the metal ion as the center of the whole system, then we can most simply place the molecules bound to it at the corners of an octahedron" (1). His initial concept is illustrated in Figure 1, wherein the soluble metal ion (M) exists in a hydrato-complex bound to a number of water molecules in water with the negative oxygen of the water dipole oriented towards the positive metal. This results in a certain spatial configuration of the donor ligand around the central metal atom.

In the ensuing years, from 1894 through 1914, Werner refined his concepto Ultimately, he concluded that the cation was characterized by two valences. The first of these he termed the "principal valency". This corresponds to the oxidation state, or oxidation number of the metal. Werner's second valency was called the "auxiliary valency". This referred to the number of atoms from the ligand associated with the central metal ion and today is known as the coordination number of the metal (2-7).

A few years later, in 1920, Morgan and Drew applied the term "chelate" to the molecular structure postulated by Werner (8). In order to form a chelate, it was recognized that the ligand must have two points of attachment to the metal ion. It was this caliper-like mode of attachment that led to the use of the Greek word "chele", meaning lobster claw, to describe how the ligand was attached to the metal ion. When the claw, or ligand, held the cation, the metal was restricted in its ability to enter into other chemical reactions. Once chelated, the metal's chemical and physical characteristics changed (9). The metal chelates are coordination compounds in contrast to metal salts where the cation is bound by electrostatic attraction. In a chelate, the ligand donates electrons to the cation. More than one donor atom must come from the ligand so that a heterocyclic ring is formed with the metal being part of that ring. Comprehension of the structure and characteristics of metal chelates has had far reaching consequences in medicine, biology, chemistry, environmental chemistry, and, particularly, nutrition, due to the stability of the metallic molecule formed.

FIGURE 1

Complexation of a metal by water in an octahedral geometry as described by Werner

The American Association of Feed Control Officials (AAFCO), an organization composed from all 50 individual state (U.S.) chemists and the United States and Canadian Food and Drug Administrations, have officially defined a metal amino acid chelate as "the product resulting from the reaction of a metal ion from a soluble salt with amino acids with a mole ratio of one mole of metal to one to three (preferably two) moles of amino acids to form coordinate covalent bonds. The average weight of the hydrolyzed amino acids must be approximately 150 and the resulting molecular weight of the chelate must not exceed 800" (10). This definition states that the metal and amino acids must be reacted before a chelate can be formed.

Since, by definition, the formation of a chelate requires chemical reactions to occur, four inviolate chemical requirements must be met. If any one of the four criteria is not fulfilled, the resulting molecule will not be a chelate, but simply a metal complex, a salt, or perhaps even an admixture.

The first of these criteria requires that the ligand must possess two functional groups, each capable of donating electrons to bond with the metal ion (11). The elements in the ligand that commonly function as donors are the more electronegative ones in the right hand side of the periodic table, primarily in Group V (12,13). The most important of these ligands contain N or O or both (14). The donor atoms may form a part of either an acidic or a basic functional group. Additionally, approximately 65% of the various types of amino acid sirle chains contain potential metal binding sites such as the sulfuydryls and hydroxyls binding groups. The common backbone of the naturally occurring amino acids contain the α-carboxyl and α-amino groups each of which can bind metal ions (11). In an aqueous environment the α-amino acid exists in the zwitterionic state with both the α-carboxyl and the α-amino groups ionized with opposite charges. Both reactive groups can thus participate in the chelation of the metal ion. The carboxyl group contains an electron that can be shared with the metal ion through a covalent bond. While the amino group has a pair of electrons that can be donated to the metal ion to form a coordinate covalent bond. The amino acid ligand is considered to be bidentate. The amino moiety meets the criteria of Lewis base when joined to the metal in accordance to current chemistry theory.

There are three classes of bidentate ligands: (1) two basic groups, (2) one acidic and one basic group, and (3) two acidic groups. Amino acids fall into the second category of bidentate ligands. Using glycine (NH₂CH₂COOH) as an example, in water at a pH of between 3 and 9, this ligand exists as the zwitterion, H₃N⁺CH₂COO-. The amino acid has lost a proton from the COOH group and is thus capable of chelating a metal ion and forming a five member ring through donation of one or more electrons to the metal (15).

A second prerequisite for chelation to occur requires that the functional groups of the ligand be located so that a ring structure can be formed with the metal atom being the closing member of the ring (12). Logically if the ligand has two donor atoms that must attach to a single metal ion, then a ring structure must be formed. Due to the nature of the elemental constituents of the ring members, this ring, by definition, must be heterocyclic. The formation of a ferrous bis-glycinate chelate is shown in Figure 2 and illustrates this concept.

FIGURE 2

The formation of ferrous bis-glucinate chelate from two ligands of glycine and a ferrous (+2) iron atom. The resulting chelate rings are five member, heterocyclic rings

Each heterocyclic ring in Figure 2 contains two bonds which extend between the ferrous ion and the glycine ligand in each ring. The first bond between the cation and the anionic, or polar portion, of the ligand is covalent in nature because they share one electron from the carboxyl group and one electron from the ferrous ion. This is the bond between the oxygen from the COO^- group, and the Fe⁺⁺. The second bond is a coordinate covalent bond. In this case, the iron behaves as Lewis acid, and the glycine as a Lewis base. The donation of both electrons from the same atom in the amino group of the ligand to the metal ion establishes the coordinate covalent bond. This donation of electrons will go to the lowest energy orbital of the iron ion that is unfilled, which in this case is a p-orbital (15,16).

The third requirement for chelation to occur necessitates that the potential reaction between the metal ion and the ligand must be sterically possible. The ferrous iron has an atomic radius of between 74 and 77 nanometers (nm) making it one of the larger transition metal ion s (17,18). Nevertheless, it is not a large cation when compared to many other ions, such as the alkaline earth metal ions. The size depends on either high spin or low spin configurations according to the magnitude of the surrounding ligand field. All non-heme iron ions are high spin (20). The larger the metal ion the greater the number of ligands that can surround it and still have contact with the metal ion (17).

The size of the ligand will also affect the stereochemistry of the chelate. While one ligand may be able to attach itself to a metal ion without problem, the addition of a second or third may be prevented by a clash between the first ligand and parts of the second or third when the latter ligands attempt to position themselves properly for attachment (12). In the case of the ferrous bis-glycinate chelate formed from the reaction in Figure 2, only the amino acid backbone is involved in the bonding of the ligand to the ferrous ion. This results in the amino acid backbone assuming a configuration that sterically allows it to function as a ligand without straining the bonds within the amino acid.

Using x-ray diffraction spectrometry, it has been determined that when the two glycine ligands are chelated to the ferrous ion, the ligands orient themselves in the least sterically hindered conformation possible. The covalent and coordinate covalent bonds are tied to the metal at uniform tetrahedral angles (11,21,22). Figure 3 illustrates a ferrous bis-glycinate chelate molecule drawn from a computer generated model that employed thermodynamic algorithms 10 determine the most thermodynamically stable configuration. This figure is consistent with the models previously developed by Pettit and Hefford describing the steric orientation of amino acid ligand in this class of bidentate chelates and with x-ray diffraction studies of known chelates (22,23).

The fourth requirement for chelation to occur is that the potential reaction between the metal ion and ligands must be energetically possible. As noted by Werner, the charge on a metal ion influences its coordination number. If this charge is low, then only a few lone pairs of electrons from a small number of ligands could prevent the bonding of greater numbers of ligands. Where the bonding between the metal and the ligand is primarily covalent, as in the case of an amino acid chelate, the coordination number of the metal is determined by the number of bonding orbitals available on the metal for combination with the ligand orbitals (19). In the case of the ferrous ion, it is satisfied by a bonding of two glycine ligands as demonstrated in Figure 2. If a molar ratio (ligand to iron) of one glycine molecule or less is employed in the reaction, the ferrous ion has the capability of being bonded to some other ligand which may ultimately displace or interfere with chelation by the original glycine ligand. Thus in most situations a ferrous bis-glycinate chelate is relatively stable since the charges on both the ion and ligands are balanced and the molar ratio of ligand to metal is stoichiometrically correcto However in the presence of a strong oxidizer or reducer, the valency of the metal may change.

FIGURE 3
Ferrous bis-glycinate chelate drawn to correctly depict the tetrahedral relationship of the bonds of O, N, C and the metal and the resulting perpendicular orientation of the two ligand ring structures. The figure is based on x-ray diffraction spectrometry of pure metal – bis-glucinate chelate crystals

Not all chelates of iron have equal bioavailability. Chelation does not guarantee mineral absorption from the gut or its subsequent metabolism if absorbed (24). After comparing various iron chelates (EDTA, fructose, citric acid) to ferrous sulfate, Bates, et al. concluded, "Chelation does not, in itself, ensure efficient uptake [of iron]. . . " (25). Rubin et al. reported that an EDTA chelate of iron may bypass the normal absorptive mechanism in the intestines and be absorbed by diffusion, but due to its high stability constant most of that EDTA chelated iron later appears in the urine unmetabolized (26,27). Because some FeEDTA is absorbed intact through the intestine but subsequently deposited in the urine, Kratzer and Vohra report this form of iron cannot be effectively used in the treatment of anemia (28). In order for mineral absorption and metabolism to occur, the chelate must be nutritionally functional. There are several criteria that must be met for a chelate to be classified as a nutritionally functional chelate.

The first of these requirements is that the iron chelate must have a low molecular weight. In 1970, it was suggested that in order for an iron amino acid chelate to cross cell ( membranes intact it must have a molecular weight of less , than 1500 daltons (29). Subsequently, others have reported that small molecular weight chelates facilitate the transfer of iron from serum to tissues (30). Kratzer and Vohra reported ( that in order for a ligand from a chelate to promote metal absorption (which goes beyond simply protecting the metal t ion in the gastrointestinal tract), it must have a molecular weight of under 1000 daltons. They have added that the higher molecular weight metalloproteins, such as ferritin or hemosiderin facilitate storage of the absorbed iron but suggested that these proteinaceous ligands are too large for intact transport of the iron molecule across cell membranes. For the transfer to occur the iron must be removed from the protein complex and bonded to another ligand that has a lower molecular weight (28).

It is relatively easy to calculate the molecular weight of a ferrous bis-g1ycinate chelate. The iron atom has an atomic weight of about 56 daltons. Each glycine ligand has a molecular weight of 75 daltons. Thus using the formula illustrated in Figure 2, the ferrous bis-glycinate chelate has molecular weight of about 204 daltons. This molecular weight has been confirmed in the laboratory (31). This in turn confirms that the molecular weight of the ferrous bis-glycinate chelate is well below the maximum molecular weight of 800 daltons established by AAFCO for a molecule to be classified as an amino acid chelate and well below the postulated absorptive limits (10,29,30).

The second requirement for a nutritionally functional chelate relates to its stability constant. If fue chelate is to be classified as nutritionally functional, it must have a stability constant that is higher than the potential formation constants of the ligands in the intestinal chyme. This higher stability constant of the amino acid chelate prevents the molecule from being destroyed in the gut and allows the chelate to cross the intestinal cell membrane intact with the metal. Once absorbed into the mucosal cell, a nutritionally functional chelate must have a stability constant which is lower than those ligands in the storage systems of the mucosal cells and the transport systems that deliver the iron to target tissues (29). In this way, the chelate can be metabolized (degraded into the ligands and metal) after absorption across the mucosal cell membrane, and still participate in the regulatory pathways of the metal.

The stability constant can be affected by the size of the chelate ring. Ligands, which form saturated five and unsaturated six member rings are the most stable (32). The glycine ligand forms a saturated five member ring with the ferrous ion.

The number of chelate rings that can potentially be formed with one carian will also affect stability. As the number of rings increase, so does stability of the molecule (32). This concept, of course, is limited by sterochemistry and the valence state of the cation. If a ligand is too large to allow the bonding of a second ligand, then chelate stability may be sacrificed. So too, if the valence of the cation exceeds that of the available ligand(s), stability is reduced. The ferrous bis-glycinate has the ideal combination. The +2 charges of the ferrous iron are satisfied with an equal number of glycine ligands that each have a -1 change.

The Lewis basic strength of the ligand will also affect stability. The greater Lewis basicity of the ligand, the more stable the resulting chelate molecule (32). Glycine is an weak Lewis base, overall. This moderates the stability of the bis- glycinate chelate, and while it is more stable than the food ligands, it has a lower stability constant than the iron storage and transport ligands in the body. In a study in which ⁵⁹FeSO₄ and ⁵⁵Fe bis-glycinate chelate were mixed in a cornmeal porridge and fed to 10 volunteers at breakfast, the absorption of the iron from the chelate was significantly (p<0.00 1) higher (5.3 times) than was iron absorption from the sulfate. There was no exchange of the radiolabelled irons from the ferrous bis-glycinate chelate and ferrous sulfate in the intestinal pool before absorption demonstrating that this bis- glycinate chelate was not affected by food ligands and was absorbed intact into the mucosal cells (33). Once absorbed into the mucosal tissue there is significant (p<0.05) hydrolyzation of the iron amino acid chelate into its individual components: iron and amino acids with the rates of transfer to the serosa from the mucosal tissue being different for each component (34).

The size and charge of the ligands will also affect the stability of the chelate. More stable chelates are formed by smaller ligands than are formed by larger ligands (32). If a large ligand is bonded to the reactive site of a metal ion, then the number of ligands able to chelate the metal ion are restricted due to steric hindrance. As noted above, this will also decrease chelate stability. Stability constants tend to become lower as the bulk of the ligand increases, suggesting a decrease in coordination sites of the ligand to the metal due to stearic hindrance (32). Glycine is the smallest of all of the amino acids. Its size favors the stability of the chelate.